JP7482118B2 - Isoquinoline compounds for the treatment of cancer - Patents.com - Google Patents

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/740,269, filed October 2, 2018, the contents of which are incorporated herein by reference in their entirety.

The primary therapeutic modalities used by oncologists to treat cancer are surgical resection, radiation therapy, and classical chemotherapy drugs. Unfortunately, surgical resection is not a viable option for many tumors or forms of cancer. Furthermore, radiation therapy and chemotherapy drugs do not target only diseased cells, and therefore damage healthy cells. Although therapeutic agents that more specifically target tumor cells have been developed by exploiting tumor-specific expression of antigens or inappropriate expression or activation of specific proteins in tumor cells, tumor cells are prone to mutations and can become resistant to drugs that specifically target tumor cells.

New cancer treatment paradigms are emerging that harness the patient's own immune system to overcome the immunoinvasive methods used by many cancers and enhance antitumor immunity. One such approach is to inhibit negative regulators of the immune response that normally function to maintain peripheral tolerance, allowing tumor antigens to be recognized as non-self elements.

Hematopoietic progenitor kinase 1 (HPK1) is an example of a negative regulator of dendritic cell activation and T and B cell responses that can be targeted to enhance antitumor immunity. HPK1 is expressed primarily by hematopoietic cells, including early progenitors. In T cells, HPK1 is thought to negatively regulate T cell activation by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, thereby reducing the persistence of signaling in microclusters, leading to recruitment of phosphorylated SLP76 and 14-3-3 proteins that bind Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters (Lasserre et al. (2011) J Cell Biol 195(5):839-853). HPK1 can also be activated in response to prostaglandin E2, which is often secreted by tumors and contributes to tumor cell escape from the immune system.

Disclosed are 3-carbonylaminoisoquinoline compounds that are inhibitors of HPK1, compositions containing these compounds, and methods for enhancing immune responses and treating HPK1-dependent disorders such as cancer.

In one aspect, there is provided a compound of formula (I), or any variation thereof, or a salt thereof (e.g., a pharma- ceutically acceptable salt thereof), as detailed herein. There is also provided a pharmaceutical composition comprising a compound of formula (I), or any variation thereof as detailed herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or excipient.

In another aspect, there is provided a method of inhibiting HPK1 in a subject, comprising contacting HPK1 in the subject with an effective amount of a compound of formula (I), or any of the variations thereof detailed herein, or a pharma- ceutically acceptable salt thereof. There is also provided a method of enhancing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or any of the variations thereof detailed herein, or a pharma- ceutically acceptable salt thereof.

Further provided is a method of treating an HPK1-dependent disorder, comprising administering to a subject in need of treatment an effective amount of a compound of formula (I), or any variation thereof detailed herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is a human. In some embodiments, the HPK1-dependent disorder is cancer, e.g., colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma. In some embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

Also provided is a compound of formula (I), or any variation thereof as detailed herein, or a pharma- ceutically acceptable salt thereof, for use in a method for inhibiting HPK1, enhancing an immune response, or treating an HPK1-dependent disorder, such as cancer.

Also provided is the use of a compound of formula (I), or any of its variations as detailed herein, or a pharma- ceutically acceptable salt thereof, in a method as detailed herein (e.g., treating an HPK1-dependent disorder, such as cancer).

There is also provided the use of a compound of formula (I), or any variation thereof as detailed herein, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for use in a method as detailed herein (e.g., treating an HPK1-dependent disorder, such as cancer).

Also provided is a kit for treating an HPK1-dependent disorder, the kit comprising a pharmaceutical composition comprising a compound of formula (I), or any variation thereof detailed herein, or a pharma- ceutically acceptable salt thereof; and instructions for use.

In another aspect, there is provided a method for making a compound of formula (I), or any variation thereof. Also provided are compound intermediates useful in the synthesis of a compound of formula (I), or any variation thereof.

Disclosed herein are compounds of formula (I) or variations thereof, such as formulas (IA), (IB), and (IC), which are inhibitors or regulators of HPK1 (hematopoietic progenitor kinase 1), and pharmaceutical compositions thereof. As such, the compounds and compositions are useful in treating diseases and disorders mediated by HPK1. One example of a method of treatment is in subjects suffering from cancer. Not only can the compounds be used to combat cancer, but they can also be advantageously used to enhance immune responses in subjects in need of such enhancement.

The subject matter disclosed herein will now be described more fully below. However, many modifications and other embodiments of the subject matter disclosed herein described herein will occur to those skilled in the art to which the subject matter disclosed herein pertains having the benefit of the teachings presented in the foregoing description. Thus, the subject matter disclosed herein should not be limited to the specific embodiments disclosed, but rather it should be considered that modifications and other embodiments are intended to be included within the scope of the appended claims. That is, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated documents, patents, and similar materials differs from or conflicts with this application (including, but not limited to, defined terms, term usage, techniques described, etc.), this application shall control. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.
Definition

As used herein, "alkyl" means a saturated linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof, having the specified number of carbon atoms (i.e., C _1-10 means 1 to ₁₀ carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms ("C _1-20 alkyl"), 1 to 8 carbon atoms ("C _1-8 alkyl"), 1 to 6 carbon atoms ("C _1-6 alkyl"), 2 to ₆ carbon atoms ("C _2-6 alkyl"), or 1 to 4 carbon atoms ("C _{1-4 alkyl} "). Examples of alkyl groups include, but are not _limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t _- butyl, isobutyl, sec-butyl; homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

As used herein, "alkenyl" means an unsaturated linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C═C), and having the specified number of carbon atoms (i.e., C _2-10 means from 2 to 10 carbon atoms). Alkenyl groups can be in the "cis" or "trans" configuration, or in the "E" or "Z" configuration. Particular alkenyl groups are those having from 2 to 20 carbon atoms ("C _2-20 alkenyl"), those having 2 to ₈ carbon atoms ("C _2-8 alkenyl"), those having 2 to 6 carbon atoms ("C _2-6 alkenyl"), or those having 2 to 4 carbon atoms ("C _2-4 alkenyl"). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof.

As used herein, "alkynyl" means an unsaturated linear (i.e. unbranched) or branched monovalent hydrocarbon chain having at least one site of acetylenic unsaturation (i.e. having at least one moiety of the formula C≡C), or combinations thereof, having the specified number of carbon atoms (i.e., C _2-10 means from 2 to 10 carbon atoms). Particular alkynyl groups are those having from 2 to 20 carbon atoms ("C _2-20 alkynyl"), those having from 2 to 8 carbon atoms ("C _2-8 alkynyl"), those having from 2 to 6 carbon atoms ("C _2-6 alkynyl"), and those having from 2 to 4 carbon atoms ("C _2-4 alkynyl"). Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof.

As used herein, "alkylene" refers to the same residue as alkyl, but having a divalent value. Particular alkylene groups are those having 1 to 6 carbon atoms ("C _1-6 alkylene"), 1 to 5 carbon atoms ("C _1-5 alkylene"), 1 to 4 carbon atoms ("C _1-4 alkylene"), or 1 to 3 carbon atoms ("C _1-3 alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene (-CH ₂ -), ethylene (-CH ₂ -CH ₂ -), 1,3-propylene (-CH ₂ -CH ₂ -CH ₂ -), 1,2-propylene (-CH(CH ₃ )-CH ₂ -), 1,4-butylene (-CH ₂ -CH ₂ -CH ₂ -CH ₂ -).

"Alkylidene," as used herein, refers to the same residue as alkyl, but having divalency at the point of attachment and attached to the parent structure via a double bond. Particular alkylidene groups are those having 1 to 6 carbon atoms ("C _1-6 alkylidene"), 1 to 5 carbon atoms ("C _1-5 alkylidene"), 1 to 4 carbon atoms ("C _1-4 alkylidene"), or 1 to 3 carbon atoms ("C _1-3 alkylidene"). Examples of alkylene include, but are not limited to, groups such as methylidene (=CH ₂ ), ethylidene (=CH-CH ₃ ), 1-propylidene (=CH-CH ₂ -CH ₃ ), 2-propylidene (=C(CH ₃ ) ₂ ), 1-butylidene (=CH ₂ -CH ₂ -CH ₂ -CH ₃ ), and the like.

As used herein, "cycloalkyl" means a non-aromatic, saturated or unsaturated cyclic monovalent hydrocarbon structure having the specified number of carbon atoms (i.e., C _3-10 means 3 to ₁₀ carbon atoms). Cycloalkyls can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl, but exclude aryl groups. Cycloalkyls containing more than one ring can be fused, spiro, or bridged, or combinations thereof. Particular cycloalkyl groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkyls are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C _3-8 cycloalkyl"), or 3 to 6 carbon atoms ("C _3-6 alkynyl"). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.

As used herein, "aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl), which may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular (i.e., ring) carbon atoms ("C _6-14 aryl"). Aryl groups having two or more rings, in which at least one ring is non-aromatic, can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, aryl groups having two or more rings, in which at least one ring is non-aromatic, are attached to the parent structure at an aromatic ring position.

As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 annular (i.e., ring) carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, phosphorus, oxygen, and sulfur. Heteroaryl groups can have one ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl), where the fused rings may or may not be aromatic. Specific heteroaryl groups are 5-14 membered rings having 1 to 12 annular (i.e., ring) carbon atoms and 1 to 6 annular (i.e., ring) heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 5-10 membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; and 5-, 6-, or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, heteroaryls include monocyclic aromatic 5-, 6-, or 7-membered rings having 1-6 ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heteroaryls include polycyclic aromatic rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. Heteroaryl groups having two or more rings, where at least one ring is non-aromatic, can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, heteroaryl groups having two or more rings, where at least one ring is non-aromatic, are attached to the parent structure at an aromatic ring position.

As used herein, "heterocycle", "heterocyclic", or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having one ring or multiple fused rings and having 1 to 14 annular (i.e., ring) carbon atoms and 1 to 6 annular (i.e., ring) heteroatoms, such as, for example, nitrogen, phosphorus, sulfur, or oxygen. Heterocycles containing two or more rings can be fused, spiro, or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl. Particular heterocyclyl groups are 3- to 14-membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 3- to 12-membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 3- to 10-membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 3- to 8-membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; and 3- to 6-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. In one variation, heterocyclyl includes a monocyclic 3-, 4-, 5-, 6-, or 7-membered ring having 1-2, 1-3, 1-4, 1-5, or 1-6 ring carbon atoms and 1-2, 1-3, or 1-4 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. In another variation, heterocyclyl includes a polycyclic non-aromatic ring having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur.

"Halo" or "halogen" means fluoro, chloro, bromo, and/or iodo. "Haloalkyl" means an alkyl group substituted with one or more halogens, which may be the same or different. When a residue is substituted with more than one halogen, the compound can be referred to using a prefix corresponding to the number of halogen moieties attached. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc., mean an aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be the same halo, but are not necessarily the same. Thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is also referred to as a "perhaloalkyl." A preferred perhaloalkyl group is trifluoroalkyl (-CF ₃ ). Similarly, "perhaloalkoxy" means an alkoxy group in which a halogen occurs at each H in the hydrocarbon to create the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF ₃ ).

"Carbonyl" means the group C=O.

"Oxo" means the moiety =O.

"Geminal" refers to the relationship of two moieties bonded to the same atom. For example, in the residue --CH ₂ --CR ^x R ^y --, R ^x and R ^y are geminal and R ^x may be referred to as the geminal R group to R ^y .

"Vicinal" refers to the relationship of two moieties that are attached to adjacent atoms. For example, in the residue --CHR ^x -CHR ^y -, R ^x and R ^y are vicinal and R ^x is sometimes referred to as the R group that is vicinal to R ^y .

Unless otherwise specified, "optionally substituted" means that a group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, which may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1-2, 1-3, 1-4, or 1-5 substituents.

As used herein, the term "inhibitor" is intended to mean a molecule that inhibits the activity of HPK1. As used herein, "inhibit" means to reduce the activity of a target enzyme compared to the activity of that enzyme in the absence of the inhibitor. In some embodiments, the term "inhibit" means a reduction in HPK1 activity by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In another embodiment, "inhibit" means a reduction in HPK1 activity by about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, "inhibit" means a reduction in HPK1 activity by about 95% to 100%, e.g., a reduction in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such a decrease can be measured using a variety of techniques that will be recognized by those of skill in the art, including in vitro kinase assays.

As used herein, an "HPK1 antagonist" or "HPK1 inhibitor" is a molecule that reduces, inhibits, or otherwise decreases one or more of the biological activities of HPK1 (e.g., serine/threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with protein binding partners such as SLP76). Antagonism using an HPK1 antagonist does not necessarily represent complete elimination of HPK1 activity. Instead, activity can be reduced by a statistically significant amount, including, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% reduction in HPK1 activity compared to a suitable control. In some embodiments, the HPK1 antagonist reduces, inhibits, or otherwise decreases the serine/threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist reduces, inhibits, or otherwise decreases HPK1-mediated phosphorylation of SLP76 and/or Gads. The compounds disclosed herein bind directly to HPK1 and inhibit its kinase activity.

By "specific antagonist" is intended an agent that reduces, inhibits, or otherwise decreases the activity of a defined target more than the activity of an unrelated target. For example, a specific HPK1 antagonist reduces at least one biological activity of HPK1 by a statistically significant amount more than the inhibitory effect of any other protein antagonist (e.g., other serine/threonine kinase). In some embodiments, the _IC50 of the antagonist for the target is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% or less _of the IC50 of the antagonist for a non-target. The compounds disclosed herein may or may not be specific HPK1 antagonists. A specific HPK1 antagonist reduces the biological activity of HPK1 by a statistically significant amount greater than the inhibitory effect of any other protein antagonist (e.g., other serine/threonine kinases). In certain embodiments, the HPK1 antagonist specifically inhibits the serine/threonine kinase activity of HPK1. In some of these embodiments, the _IC50 of the HPK1 antagonist against HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the _IC50 of the HPK1 antagonist against another serine/threonine kinase or other type of kinase (e.g., tyrosine kinase).

As used herein, "treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reduction in one or more symptoms attributable to the disease, reduction in the extent of the disease, stabilization of the disease (e.g., preventing or slowing the progression of the disease), preventing or slowing the spread of the disease (e.g., metastasis), delaying or slowing the progression of the disease, ameliorating the disease state, providing remission of the disease (whether partial or complete), reducing the dose of one or more drugs required to treat the disease, enhancing the effect of another drug, slowing the progression of the disease, increasing quality of life, and/or prolonging survival. "Treatment" also encompasses reduction in the pathological consequences of cancer. The methods of the present invention contemplate any one or more of these aspects of treatment.

As used herein, "delaying" the progression of cancer means delaying, impeding, slowing, preventing, stabilizing, and/or postponing the progression of the disease. This delay may vary in length of time depending on the disease history and/or subject being treated. As will be apparent to one of skill in the art, a sufficient or significant delay may in effect encompass prevention, in that the subject does not develop the disease. A method that "delays" the progression of cancer is one that reduces the likelihood of disease progression in a given time frame and/or reduces the extent of disease in a given time frame compared to not using the method. Such comparisons are typically based on clinical studies using a statistically significant number of subjects. Cancer progression can be detected using standard methods such as routine physical exams, mammograms, imaging, or biopsies. Progression can also refer to the progression of disease, which may be initially undetectable, and includes onset, recurrence, and onset.

As used herein, an "at risk" subject is one who is at risk for developing cancer. A "at risk" subject may or may not have detectable disease and may or may not exhibit detectable disease prior to the treatment methods described herein. "At risk" means that the subject has one or more so-called risk factors, which are measurable parameters that correlate with the development of cancer and are described herein. Subjects who have one or more of these risk factors are more likely to develop cancer than subjects who do not have these risk factors.

As used herein, "combination therapy" refers to a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy is provided that includes a compound detailed herein and another compound. In some variations, the combination therapy optionally includes one or more pharma- ceutically acceptable carriers or excipients, non-pharma-ceutical active compounds, and/or inactive substances.

As used herein, the term "effective amount" refers to that amount of a compound of the present invention that, in combination with efficacy and toxicity parameters, should be effective in a given form of treatment. As understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses may be necessary to achieve a desired therapeutic endpoint. An effective amount may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desired or beneficial result can be achieved or is achieved. The appropriate dose of any of the co-administered compounds may be optionally lowered due to the combined action (e.g., additive or synergistic effects) of the compounds. In various embodiments, an effective amount of the composition or treatment can (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, impede, delay, and preferably stop, to some extent, the infiltration of cancer cells into peripheral organs; (iv) inhibit (e.g., delay, and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the onset and/or recurrence of tumors; and/or (vii) alleviate to some extent one or more symptoms associated with cancer. In various embodiments, the amount is sufficient to alleviate, alleviate, reduce, and/or delay one or more symptoms of cancer.

As is understood in the art, an "effective amount" can be one or more doses, i.e., a single dose or multiple doses may be necessary to achieve a desired therapeutic endpoint. An effective amount may be considered in the context of administration of one or more therapeutic agents, and a compound, or pharma- ceutically acceptable salts thereof, and may be considered to be given in an effective amount if, together with one or more other agents, a desired or beneficial result can be or is achieved.

"Therapeutically effective amount" means an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome (e.g., a decrease/reduction in the severity or duration of cancer, a stabilization of the severity of cancer, or the elimination of one or more symptoms of cancer). With respect to therapeutic use, beneficial or desired results include, for example, a decrease in one or more symptoms (biochemical, histological, and/or behavioral) caused by the disease, including complications and intermediate pathological phenotypes manifested during disease progression, an increase in the quality of life of a subject suffering from the disease, a reduction in the dosage of other drugs required to treat the disease, an enhancing effect of another drug, a delay in the progression of the disease, and/or an increase in the survival of a patient.

"Prophylactically effective amount" means an amount of a compound, or a pharma- ceutically acceptable salt thereof, sufficient to prevent or reduce the severity of one or more future symptoms of cancer when administered to a subject susceptible to cancer and/or capable of developing cancer. For prophylactic use, beneficial or desirable results include, for example, elimination or reduction of risk, reduction in the severity of future disease, or delay in onset of disease (e.g., delay in biochemical, histological, and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that present during future progression of the disease).

It is understood that an effective amount, including a prophylactically effective amount, of a compound or a pharma- ceutically acceptable salt thereof may be given to a subject in an adjuvant setting, which refers to a clinical setting in which a subject has a history of cancer and is generally (but not necessarily) responsive to treatment, including but not limited to surgery (e.g., surgical resection), radiation therapy, and chemotherapy. However, because of their history of cancer, these subjects are considered to be at risk for progression of the cancer. Treatment or administration in the "adjuvant setting" refers to a subsequent mode of treatment.

As used herein, "unit dosage form" means a physically discrete unit suitable as a unitary dose, each unit containing a predetermined amount of active ingredient(s) calculated to produce a desired therapeutic effect in association with the required pharmaceutical carriers or excipients. Unit dosage forms may contain single or combination therapies.

As used herein, the term "controlled release" refers to a drug-containing formulation or fraction thereof in which the release of the drug is not immediate, i.e., including "controlled release" formulations, administration does not result in the immediate release of the drug into an absorption pool. The term encompasses depot formulations, which are designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems that generally involve mixing the drug compound with a carrier, polymer, or other compound having the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, etc.) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, etc.).

As used herein, "pharmacologically acceptable" or "pharmacologically acceptable" means a material that is not biologically or otherwise undesirable, e.g., the material can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. A pharma-ceutically acceptable carrier or excipient preferably meets the standards required for toxicity and manufacturing testing and/or is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

In some embodiments, the salts of the compounds of the invention are pharma- ceutically acceptable salts. A "pharma-ceutically acceptable salt" is one that retains at least the biological activity of the free (non-salt) compound and can be administered to a subject as a drug or pharmaceutical. Examples of such salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids, such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, and the like; and (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, such as an alkali metal, alkaline earth ion, or aluminum ion, or coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ during the manufacturing process or by separately reacting purified compounds of the invention in their free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt so formed during subsequent purification.

The term "excipient" as used herein means an inert or inactive substance that can be used in the manufacture of a drug or pharmaceutical product, e.g., a tablet containing a compound of the present invention as an active ingredient. A variety of substances can be encompassed by the term "excipient," including, but not limited to, any substance used as a binder, disintegrant, coating agent, compression/encapsulation aid, cream or lotion, lubricant, parenteral administration solution, chewable tablet material, sweetener or flavor, suspending/gelling agent, or wet granulating agent. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coating materials include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation materials include, for example, calcium carbonate, dextrose, fructose dc (dc--"directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, , maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, dextrose, fructose dc, sorbitol, sucrose dc, etc.; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the terms "excipient" and "carrier" are used interchangeably.

The term "subject" or "patient" refers to an animal, such as a mammal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In certain embodiments, the subject is a human or a human patient.

The terms "abnormal cell growth," "uncontrolled cell growth," and "hyperproliferative disorder" are used interchangeably in this application. As used herein, "abnormal cell growth" means cell growth that is independent of normal control mechanisms (e.g., loss of contact inhibition), unless otherwise specified.

The term "cancer" refers to a condition in a subject characterized by uncontrolled cell proliferation, in which cancerous cells are capable of local invasion and/or metastasis to non-adjacent sites. As used herein, "cancer cell," "cancerous cell," or "tumor cell" refers to a cell characterized by this uncontrolled cell proliferation and invasiveness. The term "cancer" encompasses all types of cancer, including, but not limited to, all forms of carcinoma, melanoma, blastoma, sarcoma, lymphoma, and leukemia, including, but not limited to, bladder cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, uterine cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal and thyroid cancer, acute lymphocytic leukemia, acute myeloid leukemia, ependymoma, Ewing's sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rod carcinoma, and nephroblastoma (Wilm's tumor).

A "chemotherapeutic agent" is a chemical compound or biological agent useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelanamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bromide, cyclophosphamide, and cyclophosphamide); latacin and blatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; camptothecin (synthetic analogs topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; pemetrexed; kallistatin; CC-1065 (its adzere Synthetic analogs of cryptophycin, carzelesin, and bizelesin; podophyllotoxin; podophyllic acid; teniposide; cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (synthetic analogs, such as KW-2189 and CB1-TM1); erytherobin; pancratistatin; TLK-286; the oral alpha-4 integrin inhibitor CDP323; sarcodictyin; spongistatin; chlorambucil, chlornaphazine, colofosfamide, erythematosin; nitrogen mustards, such as stramstine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; enediyne antibiotics, such as the calicheamicins, particularly calicheamicin γ1I and calicheamicin ω11 (see, e.g., Nicolaou et al., Angew. Chem. Intl. Ed. Engl., 33:183-186 (1994)); dynemicins, including dynemicin A; esperamicins, and the neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (ADRIAMYCIN®, morpholino-doxorubicin, cytomy ... Anomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin hydrochloride liposome injection (DOXIL® and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; methotrexate, gemcitabine (GEMZAR®), tegafur ( UFTORAL®), capecitabine (XELODA®), epothilones, and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridinene, doxifluridine, enocitabine, and floxiridine; antiadrenal agents such as aminoglutethimide, mitotein, and trilostane; folic acid supplements such as folinic acid; Seguratone; Aldophosphamide glycosides; Aminolevulinic acid; Eniluracil; Amsacrine; Bestravcil; Bisantrene; Edatrexate; Defofamine; Demecolcine; Diaziquone; Eflornithine; Elliptinium acetate; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids such as maytansine and ansamitocins; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerin; Pentostatin; Phenamet; Pirarubicin; Rosoxantrone; 2-Ethylhydrazide; Procarbazine; PSK® Polysaccharide Complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; schizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannommustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa; taxoids, e.g. paclitaxel (TAXOL®), albumin recombinant forms of paclitaxel Nanoparticle formulations (ABRAXANE™), and docetaxel (TAXOTERE®); chlorambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine (VELBAN®); platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; folinic acid; vinorelbine (NAVELBINE®); novantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitors RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharma- ceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (short for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone) and FOLFOX (short for a treatment regimen with oxaliplatin (ELOXATIN™) in combination with 5-FU and folinic acid).

Further examples of chemotherapeutic agents include "anti-hormones" that act to control, reduce, block, or inhibit the effectiveness of hormones that may promote the growth of cancer, often in the form of systemic or whole-body treatments. They may themselves be hormones. Examples include anti-estrogens and selective estrogen receptor regulators (SERMs), such as tamoxifen (including NOLVADEX® tamoxifen), raloxifene (EVISTA®), droloxifene, 4-hydroxytamoxifen, trioxyfene, keoxyfene, LY117018, onapristone, and toremifene (FARESTON®); anti-progesterones; estrogen receptor downregulators (ERDs); estrogen receptor antagonists such as fulvestrant (FASLODEX®); agents that function to suppress or shut down the ovaries, such as leuprolide acetate (LUPRON® and ELIGOR®); and aromatase inhibitors that inhibit the enzyme aromatase, which controls estrogen production in the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGASE®), exemestane (AROMASIN®), holmestein, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®). Further chemotherapeutic agents as defined above include clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); as well as troxacitabine (1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways implicated in adherent cell proliferation, such as PKC-α, Raf, H-Ra s, and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccines, and gene therapy vaccines, such as ALLOVECTIIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitors (e.g., LURTOTECAN®); antiestrogens such as fulvestrant; EGFR inhibitors such as erlotinib or cetuximab; anti-VEGF inhibitors such as bevacizumab; alinotecan; rmRH (e.g., ABARELIX®); 17AAG (a geldanamycin derivative that is a heat shock protein (Hsp) 90 poison), and pharma- ceutically acceptable salts, acids, or derivatives of any of the above.

The definition of "chemotherapeutic agent" also includes: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (NOLVADEX®; including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); (ii) anti-adrenal gland agents that act to regulate or inhibit hormone action on tumors, such as anti-estrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (NOLVADEX®; including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY117018, onapristone, and FARESTON® (toremifene citrate); aromatase inhibitors, which inhibit the enzyme aromatase, which regulates estrogen production in the body, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestani, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens, For example, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as, for example, PKC-alpha, Ralf, and H-Ras; (vii) VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors. (viii) gene therapy vaccines, e.g., vaccines such as ALLOVECTIIN®, LEUVECTIN®, and VAXID®; topoisomerase 1 inhibitors such as PROLEUKIN® rIL-2; LURTOTECAN®; ABARELIX® rmRH; (ix) antiangiogenic agents such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

In some embodiments, the chemotherapeutic agent is an immunotherapeutic agent. As used herein, an "immunotherapeutic agent" is a compound that enhances the immune system to specifically or non-specifically help fight cancer. Immunotherapeutic agents include monoclonal antibodies and non-specific immunotherapies that boost the immune system, such as cytokines, interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-21), interferons (e.g., IFN-α, IFN-β, IFN-γ), GM-CSF, thalidomide (THALOMID®, Celgene), lenalidomide (REVLIMID®, Celgene), pomalidomide (POMALYST®, Celgene), imiquimod (ZYCLARA®, Valeant), etc. Non-limiting examples of monoclonal antibodies useful as chemotherapeutic agents include trastuzumab (HERCEPTIN®, Genentech), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Bristol-Myers Squibb), panitumumab (VECTIBIX®, Amgen), ipilimumab (YERVOY®, Bristol-Myers Squibb), and rifampinib (RIF®, Bristol-Myers Squibb). Squibb), rituximab (RITUXAN®, Genentech), alemtuzumab (CAMPATH®, Genzyme), ofatumumab (ARZERRA®, Genmab), gemtuzumab ozogamicin (MYLOTARG®, Wyeth), brentuximab vedotin (ADCETRIS®, Seattle Genetics), ⁹⁰ Y-labeled ibritumomab tiuxetan (ZEVALIN®, Biogen Idec), ¹³¹ I-labeled tositumomab (BEXXAR®, GlaxoSmithKline), ado-trastuzumab emtansine (KADCYLA®, Genentech), blinatumomab (BLINCYTO®, Amgen), pertuzumab (PERJETA®, Genentech), obinutuzumab (GAZYVA®, Genentech), nivolumab (OPDIVO®, Bristol-Myers Squibb), Squibb), pembrolizumab (KEYTRUDA®, Merck), pidilizumab (CureTech), MPDL3280A (described in WO 2010/077634, which is incorporated herein by reference in its entirety), MDX-1105 (described in WO 2007/005874, which is incorporated herein by reference in its entirety), and MEDI4736 (described in WO 2011/066389 and U.S. Patent Application Publication No. 2013/034559, each of which is incorporated herein by reference in its entirety). Another useful immunotherapeutic is AMP-224 (described in WO 2010/027827 and WO 2011/066342, each of which is incorporated herein by reference in its entirety).

Compound

The compounds disclosed herein are 3-carbonylaminoisoquinoline compounds of formula (I), or salts (e.g., pharma- ceutically acceptable salts), solvates (e.g., hydrates), prodrugs, metabolites, or derivatives thereof. These compounds are useful as inhibitors of HPK1.

式中、
Ｒ^１は、水素、ハロゲン、ヒドロキシル、Ｃ_１－６アルキル、Ｃ_１－６ハロアルキル、Ｃ_３－４シクロアルキル、－Ｏ（Ｃ_１－６アルキル）、又は－Ｏ（Ｃ_１－６ハロアルキル）であり、
Ｒ^１５は、－ＯＲ^１６、－ＳＲ^１６、－ＮＲ^１７Ｒ^１８、又はＤであり、
各Ｒ^１６は、独立してＣ_１－６アルキル、Ｃ_３－１０シクロアルキル、又は３～１４員のヘテロシクリルであり、Ｒ^１６のＣ_１－６アルキル、Ｃ_３－１０シクロアルキル、及び３～１４員のヘテロシクリルは、それぞれ独立して、Ｒ^１０から独立して選択される１、２、３、４、又は５個の置換基で任意に置換され、
Ｒ^１７は、水素又はＣ_１－６アルキルであり、
Ｒ^１８は、Ｒ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換された３～１４員のヘテロシクリル；Ｒ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換されたＣ_３－１０シクロアルキル；若しくはＲ^１０から独立して選択される１、２、３、４若しくは５個の置換基で置換されたＣ_１－６アルキルであるか、
又は、Ｒ^１７及びＲ^１８は、それらが結合する窒素原子と共に、Ｒ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換された４～１２員のヘテロシクリルを形成し、
Ｄは、

であり、式中、波線は親構造への結合点を表し、
Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４は、独立して水素又はＲ^１０であり、任意にＲ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４のうちの２つは、それらが結合する炭素原子と共に、Ｒ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換されたＣ_３－８シクロアルキル又はＲ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換された３～１０員のヘテロシクリルを形成し、但し、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４のうちの少なくとも１つは水素以外であり、
Ｒ^３は、水素、ハロゲン、シアノ、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、３～１４員のヘテロシクリル、又は－ＯＲ^７であり、Ｒ^３のＣ_１－６アルキル、Ｃ_３－８シクロアルキル、及び３～１４員のヘテロシクリルは、それぞれ、Ｒ^１０から独立して選択される１、２、３、４、又は５個の置換基で任意に置換され、
Ｒ^４は、Ｒ^１０から独立して選択される１、２、３、４、又は５個の置換基で任意に置換された５～１４員のヘテロアリールであり、
Ｒ^５は、水素、ハロゲン、シアノ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－８シクロアルキル、Ｃ_６－１４アリール、５～１４員のヘテロアリール、３～１４員のヘテロシクリル、－Ｃ（Ｏ）Ｒ^６、－Ｃ（Ｏ）ＯＲ^７、－Ｃ（Ｏ）ＮＲ^８ａＲ^８ｂ、－ＯＲ^７、－ＯＣ（Ｏ）Ｒ^６、－ＯＣ（Ｏ）ＮＲ^８ａＲ^８ｂ、－ＳＲ^７、－Ｓ（Ｏ）Ｒ^９、－Ｓ（Ｏ）_２Ｒ^９、－Ｓ（Ｏ）_２ＮＲ^８ａＲ^８ｂ、－Ｐ（Ｏ）Ｒ^９ａＲ^９ｂ、－ＮＲ^８ａＲ^８ｂ、－Ｎ（Ｒ^８）Ｃ（Ｏ）Ｒ^６、－Ｎ（Ｒ^８）Ｃ（Ｏ）ＯＲ^７、－Ｎ（Ｒ^８）Ｃ（Ｏ）ＮＲ^８ａＲ^８ｂ、－Ｎ（Ｒ^８）Ｓ（Ｏ）_２Ｒ^９、又は－Ｎ（Ｒ^８）Ｓ（Ｏ）_２ＮＲ^８ａＲ^８ｂであり、Ｒ^５のＣ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－８シクロアルキル、Ｃ_６－１４アリール、５～１４員のヘテロアリール及び３～１４員のヘテロシクリルは、それぞれ、Ｒ^１０から独立して選択される１、２、３、４又は５個の置換基で任意に置換され、
各Ｒ^６は、独立して水素、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、又は３～１２員のヘテロシクリルであり、Ｒ^６のＣ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１０から独立して選択される１、２、３、４、又は５個の置換基で任意に置換され、
各Ｒ^７は、独立して水素、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、又は３～１２員のヘテロシクリルであり、Ｒ^７のＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１０から独立して選択される１、２、３、４、又は５個の置換基で任意に置換され、
各Ｒ^８は、独立して水素又はＣ_１－６アルキルであり、
各Ｒ^８ａ及びＲ^８ｂは、独立して水素、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、若しくは３～１２員のヘテロシクリルであり、Ｒ^８ａ及びＲ^８ｂのＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１０から独立して選択される１、２、３、４、若しくは５個の置換基で任意に置換されるか、
又は、Ｒ^８ａ及びＲ^８ｂは、それらが結合する窒素原子と共に、Ｒ^１０から独立して選択される１、２、３、４、若しくは５個の置換基で任意に置換された４～１２員のヘテロシクリルを形成し、
各Ｒ^９は、独立してＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、又は３～１２員のヘテロシクリルであり、Ｒ^９のＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１０から独立して選択される１、２、３、４、又は５個の置換基で任意に置換され、
各Ｒ^９ａ及びＲ^９ｂは、独立してＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、３～１２員のヘテロシクリル、若しくは－Ｏ－Ｃ_１－６アルキルであり、Ｒ^９ａ及びＲ^９ｂのＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１０から独立して選択される１、２、３、４、若しくは５個の置換基で任意に置換されるか、
又は、Ｒ^９ａ及びＲ^９ｂは、それらが結合するリン原子と共に、Ｒ^１０から独立して選択される１、２、３、４、若しくは５個の置換基で任意に置換された４～１２員のヘテロシクリルを形成し、
各Ｒ^１０は、独立してオキソ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、３～１２員のヘテロシクリル、ハロゲン、シアノ、－Ｃ（Ｏ）Ｒ^ａ、－Ｃ（Ｏ）ＯＲ^ｂ、－Ｃ（Ｏ）ＮＲ^ｃＲ^ｄ、－ＯＲ^ｂ、－ＯＣ（Ｏ）Ｒ^ａ、－ＯＣ（Ｏ）ＮＲ^ｃＲ^ｄ、－ＳＲ^ｂ、－Ｓ（Ｏ）Ｒ^ｅ、－Ｓ（Ｏ）_２Ｒ^ｅ、－Ｓ（Ｏ）（＝ＮＨ）Ｒ^ｅ、－Ｓ（Ｏ）_２ＮＲ^ｃＲ^ｄ、－ＮＲ^ｃＲ^ｄ、－Ｎ（Ｒ^ｆ）Ｃ（Ｏ）Ｒ^ａ、－Ｎ（Ｒ^ｆ）Ｃ（Ｏ）ＯＲ^ｂ、－Ｎ（Ｒ^ｆ）Ｃ（Ｏ）ＮＲ^ｃＲ^ｄ、－Ｎ（Ｒ^ｆ）Ｓ（Ｏ）_２Ｒ^ｅ、－Ｎ（Ｒ^ｆ）Ｓ（Ｏ）_２ＮＲ^ｃＲ^ｄ、又は－Ｐ（Ｏ）Ｒ^ｇＲ^ｈであり、Ｒ^１０のＣ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、及び３～１４員のヘテロシクリルは、Ｒ^１１から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ａは、独立して水素、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、又は３～１２員のヘテロシクリルであり、Ｒ^ａのＣ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１１から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｂは、独立して水素、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、又は３～１２員のヘテロシクリルであり、Ｒ^ｂのＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１１から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｃ及びＲ^ｄは、独立して水素、Ｃ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、若しくは３～１２員のヘテロシクリルであり、Ｒ^ｃ及びＲ^ｄのＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１１から独立して選択される１、２、３、若しくは４個の置換基で任意に置換されるか、
又は、Ｒ^ｃ及びＲ^ｄは、それらが結合する窒素原子と共に、Ｒ^１１から独立して選択される１、２、３、若しくは４個の置換基で任意に置換された４～１２員のヘテロシクリルを形成し、
各Ｒ^ｅは、独立してＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、又は３～１２員のヘテロシクリルであり、Ｒ^ｅのＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１１から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｆは、独立して水素又はＣ_１－６アルキルであり、
各Ｒ^ｇ及びＲ^ｈは、独立してＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、３～１２員のヘテロシクリル、若しくは－Ｏ－Ｃ_１－６アルキルであり、Ｒ^ｇ及びＲ^ｈのＣ_１－６アルキル、Ｃ_３－８シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～１２員のヘテロシクリルは、それぞれ、Ｒ^１１から独立して選択される１、２、３、若しくは４個の置換基で任意に置換されるか、
又は、Ｒ^ｇ及びＲ^ｈは、それらが結合するリン原子と共に、Ｒ^１１から独立して選択される１、２、３、若しくは４個の置換基で任意に置換された４～１２員のヘテロシクリルを形成し、
各Ｒ^１１は、独立してオキソ、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、３～８員のヘテロシクリル、ハロゲン、シアノ、－Ｃ（Ｏ）Ｒ^ａ１、－Ｃ（Ｏ）ＯＲ^ｂ１、－Ｃ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、－ＯＲ^ｂ１、－ＯＣ（Ｏ）Ｒ^ａ１、－ＯＣ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、－ＳＲ^ｂ１、－Ｓ（Ｏ）Ｒ^ｅ１、－Ｓ（Ｏ）_２Ｒ^ｅ１、－Ｓ（Ｏ）_２ＮＲ^ｃ１Ｒ^ｄ１、－ＮＲ^ｃ１Ｒ^ｄ１、－Ｎ（Ｒ^ｆ１）Ｃ（Ｏ）Ｒ^ａ１、－Ｎ（Ｒ^ｆ１）Ｃ（Ｏ）ＯＲ^ｂ１、－Ｎ（Ｒ^ｆ１）Ｃ（Ｏ）ＮＲ^ｃ１Ｒ^ｄ１、－Ｎ（Ｒ^ｆ１）Ｓ（Ｏ）_２Ｒ^ｅ１、－Ｎ（Ｒ^ｆ１）Ｓ（Ｏ）_２ＮＲ^ｃ１Ｒ^ｄ１、又は－Ｐ（Ｏ）Ｒ^ｇ１Ｒ^ｈ１であり、Ｒ^１１のＣ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１４員のヘテロアリール、及び３～１４員のヘテロシクリルは、それぞれ、Ｒ^１２から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ａ１は、独立して水素、Ｃ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、又は３～８員のヘテロシクリルであり、Ｒ^ａ１のＣ_１－６アルキル、Ｃ_２－６アルケニル、Ｃ_２－６アルキニル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～８員のヘテロシクリルは、それぞれ、Ｒ^１２から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｂ１は、独立して水素、Ｃ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、又は３～８員のヘテロシクリルであり、Ｒ^ｂ１のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～８員のヘテロシクリルは、それぞれ、Ｒ^１２から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｃ１及びＲ^ｄ１は、独立して水素、Ｃ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、若しくは３～８員のヘテロシクリルであり、Ｒ^ｃ１及びＲ^ｄ１のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～８員のヘテロシクリルは、それぞれ、Ｒ^１２から独立して選択される１、２、３、若しくは４個の置換基で任意に置換されるか、
又は、Ｒ^ｃ１及びＲ^ｄ１は、それらが結合する窒素原子と共に、Ｒ^１２から独立して選択される１、２、３、若しくは４個の置換基で任意に置換された４～８員のヘテロシクリルを形成し、
各Ｒ^ｅ１は、独立してＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、又は３～８員のヘテロシクリルであり、Ｒ^ｅ１のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～８員のヘテロシクリルは、それぞれ、Ｒ^１２から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｆ１は、独立して水素又はＣ_１－６アルキルであり、
各Ｒ^ｇ１及びＲ^ｈ１は、独立してＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、３～８員のヘテロシクリル、若しくは－Ｏ－Ｃ_１－６アルキルであり、Ｒ^ｇ１及びＲ^ｈ１のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６－１０アリール、５～１０員のヘテロアリール、及び３～８員のヘテロシクリルは、それぞれ、Ｒ^１２から独立して選択される１、２、３、若しくは４個の置換基で任意に置換されるか、
又は、Ｒ^ｇ１及びＲ^ｈ１は、それらが結合するリン原子と共に、Ｒ^１２から独立して選択される１、２、３、若しくは４個の置換基で任意に置換された４～８員のヘテロシクリルを形成し、
各Ｒ^１２は、独立してオキソ、Ｃ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６アリール、５～６員のヘテロアリール、３～６員のヘテロシクリル、ハロゲン、シアノ、－Ｃ（Ｏ）Ｒ^ａ２、－Ｃ（Ｏ）ＯＲ^ｂ２、－Ｃ（Ｏ）ＮＲ^ｃ２Ｒ^ｄ２、－ＯＲ^ｂ２、－ＯＣ（Ｏ）Ｒ^ａ２、－ＯＣ（Ｏ）ＮＲ^ｃ２Ｒ^ｄ２、－Ｓ（Ｏ）_２Ｒ^ｅ２、－Ｓ（Ｏ）_２ＮＲ^ｃ２Ｒ^ｄ２、－ＮＲ^ｃ２Ｒ^ｄ２、－Ｎ（Ｒ^ｆ２）Ｃ（Ｏ）Ｒ^ａ２、－Ｎ（Ｒ^ｆ２）Ｃ（Ｏ）ＯＲ^ｂ２、－Ｎ（Ｒ^ｆ２）Ｃ（Ｏ）ＮＲ^ｃ２Ｒ^ｄ２、－Ｎ（Ｒ^ｆ２）Ｓ（Ｏ）_２Ｒ^ｅ２、－Ｎ（Ｒ^ｆ２）Ｓ（Ｏ）_２ＮＲ^ｃ２Ｒ^ｄ２、又は－Ｐ（Ｏ）Ｒ^ｇ２Ｒ^ｈ２であり、Ｒ^１２のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６アリール、５～６員のヘテロアリール、及び３～６員のヘテロシクリルは、それぞれ、Ｒ^１３から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ａ２は、独立して水素、Ｃ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６アリール、５～６員のヘテロアリール、又は３～６員のヘテロシクリルであり、Ｒ^ａ２のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６アリール、５～６員のヘテロアリール、及び３～６員のヘテロシクリルは、それぞれ、Ｒ^１３から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｂ２は、独立して水素、Ｃ_１－６アルキル、Ｃ_３－６シクロアルキル、又は３～６員のヘテロシクリルであり、Ｒ^ｂ２のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、及び３～６員のヘテロシクリルは、それぞれ、Ｒ^１３から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｃ２及びＲ^ｄ２は、独立して水素、Ｃ_１－６アルキル、Ｃ_３－６シクロアルキル、若しくは３～８員のヘテロシクリルであり、Ｒ^ｃ２及びＲ^ｄ２のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、及び３～８員のヘテロシクリルは、それぞれ、Ｒ^１３から独立して選択される１、２、３、若しくは４個の置換基で任意に置換されるか、
又は、Ｒ^ｃ２及びＲ^ｄ２は、それらが結合する窒素原子と共に、Ｒ^１３から独立して選択される１、２、３、若しくは４個の置換基で任意に置換された４～６員のヘテロシクリルを形成し、
各Ｒ^ｅ２は、独立してＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６アリール、５～６員のヘテロアリール、又は３～６員のヘテロシクリルであり、Ｒ^ｅ２のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、Ｃ_６アリール、５～６員のヘテロアリール、及び３～６員のヘテロシクリルは、それぞれ、Ｒ^１３から独立して選択される１、２、３、又は４個の置換基で任意に置換され、
各Ｒ^ｆ２は、独立して水素又はＣ_１－６アルキルであり、
各Ｒ^ｇ２及びＲ^ｈ２は、独立してＣ_１－６アルキル、Ｃ_３－６シクロアルキル、３～８員のヘテロシクリル、若しくは－Ｏ－Ｃ_１－６アルキルであり、Ｒ^ｇ２及びＲ^ｈ２のＣ_１－６アルキル、Ｃ_３－６シクロアルキル、及び３～８員のヘテロシクリルは、それぞれ、Ｒ^１３から独立して選択される１、２、３、若しくは４個の置換基で任意に置換されるか、
又は、Ｒ^ｇ２及びＲ^ｈ２は、それらが結合するリン原子と共に、Ｒ^１３から独立して選択される１、２、３、若しくは４個の置換基で任意に置換された４～６員のヘテロシクリルを形成し、かつ
各Ｒ^１３は、独立してオキソ、ハロゲン、ヒドロキシル、－Ｏ（Ｃ_１－６アルキル）、シアノ、Ｃ_１－６アルキル、又はＣ_１－６ハロアルキルである、
の化合物、又は、その塩（例えば薬学的に許容され得る塩）、溶媒和物（例えば水和物）、プロドラッグ、代謝産物、若しくは誘導体を提供する。 In one embodiment, the compound of formula (I)

In the formula,
R ¹ is hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, C _3-4 cycloalkyl, -O(C _1-6 alkyl), or -O(C _1-6 haloalkyl);
R ¹⁵ is —OR ¹⁶ , —SR ¹⁶ , —NR ¹⁷ R ¹⁸ , or D;
each R ¹⁶ is independently a C _1-6 alkyl, a C _3-10 cycloalkyl, or a 3- to 14-membered heterocyclyl, and the C _1-6 alkyl, C _3-10 cycloalkyl, and the 3- to 14-membered heterocyclyl of R ¹⁶ are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
R ¹⁷ is hydrogen or C _1-6 alkyl;
R ¹⁸ is a 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; a C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; or a C _1-6 alkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
or R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ ;
D is

where the wavy line represents the point of attachment to the parent structure;
R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ are independently hydrogen or R ¹⁰ , and optionally two of R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ together with the carbon atom to which they are attached form a C _3-8 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ or a 3-10 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ , with the proviso that at least one of R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ is other than hydrogen;
R ³ is hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3- to 14-membered heterocyclyl, or -OR ⁷ , wherein the C _1-6 alkyl, C _3-8 cycloalkyl, and 3- to 14-membered heterocyclyl of R ³ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
R ⁴ is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
R ⁵ is hydrogen, halogen, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, -C(O)R ⁶ , -C(O)OR ⁷ , -C(O)NR ^8a R ^8b , -OR ⁷ , -OC(O)R ⁶ , -OC(O)NR ^8a R ^8b , -SR ⁷ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -S(O) ₂ NR ^8a R ^8b , -P(O)R ^9a R ^9b , -NR ^8a R ^8b , -N(R ⁸ )C(O)R ⁶ , -N(R ⁸ )C(O)OR ⁷ , —N(R ⁸ )C(O)NR ^8a R ^8b , —N(R ⁸ )S(O) ₂ R ⁹ , or —N(R ⁸ )S(O) ₂ NR ^8a R ^8b , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R ⁵ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
each R ⁶ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, and the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-12 membered heterocyclyl of R ⁶ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
each R ⁷ is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, and the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-12 membered heterocyclyl of R ⁷ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
Each R ⁸ is independently hydrogen or C _1-6 alkyl;
each R ^8a and R ^8b is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, and the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-12 membered heterocyclyl of R ^8a and R ^8b are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
or R ^8a and R ^8b together with the nitrogen atom to which they are attached form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
each R ⁹ is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, and each of the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-12 membered heterocyclyl of R ⁹ is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
each R ^9a and R ^9b is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclyl, ^or -O-C _1-6 alkyl, and the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl of R 9a and R ^9b are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
or R ^9a and R ^9b together with the phosphorus atom to which they are attached form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
Each R ¹⁰ is independently selected from oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, halogen, cyano, -C(O)R ^a , -C(O)OR ^b , -C(O)NR ^c R ^d , -OR ^b , -OC(O)R ^a , -OC(O)NR ^c R ^d , -SR ^b , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)(═NH)R ^e , -S(O) ₂ NR ^c R ^d , -NR ^c R ^d , -N(R ^f )C(O)R ^a , -N(R ^f )C(O)OR ^b , —N(R ^f )C(O)NR ^c R ^d , —N(R ^f )S(O) ₂ R ^e , —N(R ^f )S(O) ₂ NR ^c R ^d , or —P(O)R ^g R ^h ; and the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R ¹⁰ are optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
each R ^a is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, and each of the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^a is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
each R ^b is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, and each of the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^b is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
each R ^c and R ^d is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, and the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^c and R ^d are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
or R ^c and R ^d together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
each R ^e is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, and each of the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R ^e is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
Each R ^f is independently hydrogen or C _1-6 alkyl;
each R ^g and R ^h is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or -O-C _1-6 alkyl, and the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of ^R g and R ^h are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
or R ^g and R ^h together with the phosphorus atom to which they are attached form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
Each R ¹¹ is independently selected from oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, halogen, cyano, -C(O)R ^a1 , -C(O)OR ^b1 , -C(O)NR ^c1 R ^d1 , -OR ^b1 , -OC(O)R ^a1 , -OC(O)NR ^c1 R ^d1 , -SR ^b1 , -S(O)R ^e1 , -S(O) ₂ R ^e1 , -S(O) ₂ NR ^c1 R ^d1 , -NR ^c1 R ^d1 , -N(R ^f1 )C(O)R ^a1 , -N(R ^f1 )C(O)OR ^b1 , -N(R ^f1 )C(O)NR ^c1 R ^d1 , -N(R ^f1 )S(O) ₂ R ^e1 , -N(R ^f1 )S(O) ₂ NR ^c1 R ^d1 , or -P(O)R ^g1 R ^h1 , and ^the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R 11 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
each R ^a1 is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6} alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, and the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, _5-10 membered heteroaryl, and 3-8 membered heterocyclyl of R ^a1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
each R ^b1 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R ^b1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
each R ^c1 and R ^d1 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl of R ^c1 and R ^d1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
or R ^c1 and R ^d1 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
each R ^e1 is independently C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R ^e1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
Each R ^f1 is independently hydrogen or C _1-6 alkyl;
each R ^g1 and R ^h1 is independently C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, or -O-C _1-6 alkyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl of R ^g1 and R ^h1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
or R ^g1 and R ^h1 together with the phosphorus atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
Each R ¹² is independently selected from oxo, C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, halogen, cyano, -C(O)R ^a2 , -C(O)OR ^b2 , -C(O)NR ^c2 R ^d2 , -OR ^b2 , -OC(O)R ^a2 , -OC(O)NR ^c2 R ^d2 , -S(O) ₂ R ^e2 , -S(O) ₂ NR ^c2 R ^d2 , -NR ^c2 R ^d2 , -N(R ^f2 )C(O)R ^a2 , -N(R ^f2 )C(O)OR ^b2 , -N(R ^f2 )C(O)NR ^c2 R ^d2 , -N(R ^f2 )S(O) ₂ R ^e2 , -N(R ^f2 )S(O) ₂ NR ^c2 R ^d2 , or -P(O)R ^g2 R ^h2 ; and the C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of R ¹² are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
Each R ^a2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of R ^a2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
each R ^b2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3- to 6-membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, and 3- to 6-membered heterocyclyl of R ^b2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
Each R ^c2 and R ^d2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3- to 8-membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, and 3- to 8-membered heterocyclyl of R ^c2 and R ^d2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
or R ^c2 and R ^d2 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
Each R ^e2 is independently C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of R ^e2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
Each R ^f2 is independently hydrogen or C _1-6 alkyl;
each R ^g2 and R ^h2 is independently C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or -O-C _1-6 alkyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, and 3- to 8-membered heterocyclyl of R ^g2 and R ^h2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
or R ^g2 and R ^h2 , together with the phosphorus atom to which they are attached, form a 4-6 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ , and each R ¹³ is independently oxo, halogen, hydroxyl, -O(C _1-6 alkyl), cyano, C _1-6 alkyl, or C _1-6 haloalkyl;
or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., a hydrate), prodrug, metabolite, or derivative thereof.

In some embodiments, the compounds are other than the compounds of Table 1X and salts thereof. In some embodiments, the compounds herein, such as compounds of formula (I), are other than a compound selected from one or more of compound numbers 1x-24x in Table 1X. In some embodiments, the compounds herein, such as compounds of formula (I), are other than a compound selected from one or more of compound numbers 25x-161x in Table 1X. In some embodiments, the compounds of the present disclosure and methods of using the compounds detailed herein include any of the compounds of formula (I), including those listed in Table 1X and salts thereof.

In some embodiments, the compound is a compound of formula (I) where R ¹⁵ is -OR ¹⁶ , -SR ¹⁶ , -NR ¹⁷ R ¹⁸ , or D, or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof.

In some embodiments, R ¹⁵ is -OR ¹⁶ or -SR ¹⁶ , and each R ¹⁶ is independently C _1-6 alkyl, C _3-10 cycloalkyl, or 3-14 membered heterocyclyl, and the C _1-6 alkyl, C _3-10 cycloalkyl, and 3-14 membered heterocyclyl of R ¹⁶ are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In some of these embodiments, R ¹⁵ is -OR ^16. In some of these embodiments, R ¹⁵ is -SR ¹⁶ .

式中、
Ｒ^１６は、Ｃ_１－６アルキル、Ｃ_３－１０シクロアルキル、又は３～１４員のヘテロシクリルであり、Ｒ^１６のＣ_１－６アルキル、Ｃ_３－１０シクロアルキル、及び３～１４員のヘテロシクリルは、それぞれ独立して、Ｒ^１０から独立して選択される１、２、３、４、又は５個の置換基で任意に置換され、かつ
Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^１０は、式（Ｉ）、又は本明細書で詳述する変形について定義されるとおりである、
の化合物、又はその塩（例えば薬学的に許容され得る塩）を提供する。
いくつかの実施形態において、化合物は式（ＩＡ）の化合物、又はその塩（例えば、薬学的に許容され得る塩）であり、但し、化合物は、表１Ｘにおける化合物番号１ｘ、２５ｘ及び１６１ｘ、並びにその塩以外である。いくつかの実施形態において、化合物は式（ＩＡ）の化合物、又はその塩（例えば、薬学的に許容され得る塩）であり、但し、化合物は、表１Ｘにおける化合物番号１ｘ、及びその塩以外である。いくつかの実施形態において、化合物は式（ＩＡ）の化合物、又はその塩（例えば、薬学的に許容され得る塩）であり、但し、化合物は、表１Ｘにおける化合物番号２５ｘ及び１６１ｘ並びにその塩以外である。いくつかの実施形態において、Ｒ^１６はｔｅｒｔ－ブチル及びメチル以外である。いくつかの実施形態において、Ｒ^１６はｔｅｒｔ－ブチル以外である。いくつかの実施形態において、Ｒ^１６は、メチル以外である。 In one embodiment, the compound of formula (IA)

In the formula,
R ¹⁶ is a C _1-6 alkyl, a C _3-10 cycloalkyl, or a 3-14 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-10 cycloalkyl, and the 3-14 membered heterocyclyl of R ¹⁶ are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; and R ¹ , R ³ , R ⁴ , R ⁵ , and R ¹⁰ are as defined for formula (I), or any of the variations detailed herein;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).
In some embodiments, the compound is a compound of formula (IA), or a salt thereof (e.g., a pharma- ceutically acceptable salt), with the proviso that the compound is other than compound No. 1x, 25x, and 161x in Table 1X, and salts thereof. In some embodiments, the compound is a compound of formula (IA), or a salt thereof (e.g., a pharma- ceutically acceptable salt), with the proviso that the compound is other than compound No. 1x in Table 1X, and salts thereof. In some embodiments, the compound is a compound of formula (IA), or a salt thereof (e.g., a pharma- ceutically acceptable salt), with the proviso that the compound is other than compound No. 25x and 161x in Table 1X, and salts thereof. In some embodiments, ^R16 is other than tert-butyl and methyl. In some embodiments, ^R16 is other than tert-butyl. In some embodiments, ^R16 is other than methyl.

In some embodiments, the compound is a compound of Formula (I) or (IA), or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof, wherein R ¹⁶ is independently C _1-6 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; or 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ . In some embodiments, R ¹⁶ is C _1-6 alkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; or 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ .

In some embodiments, R ¹⁶ is a 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In some of these embodiments, R ¹⁶ is a 4-10 membered heterocyclyl having 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In some of these embodiments, R ¹⁶ is a 4-7 membered monocyclic heterocyclyl having 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ . In some of these embodiments, R ¹⁶ is a 6-10 membered bicyclic heterocyclyl having 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S, and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ .

In some embodiments, R ¹⁶ is C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In some embodiments, R ¹⁶ is C _3-8 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ .

In some embodiments, R ¹⁶ is C _1-6 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In some of these embodiments, R ¹⁶ is C _1-6 alkyl or C _1-6 haloalkyl. In some of these embodiments, R ¹⁶ is C 1-6 alkyl (e.g., neopentyl). In some of these embodiments, R ¹⁶ is C _1-6 alkyl substituted with 1, 2, ₃ , 4, or 5 substituents independently selected from R ^10. In one variation, R ¹⁶ is C _1-6 haloalkyl (e.g., 2,2,2-trifluoroethyl).

In some of these embodiments, R ¹⁶ is -(C _1-6 alkylene)-R ¹⁹ and R ¹⁹ is C _3-10 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, cyano, -OR ⁷ , -NR ^8a R ^8b , or -S(O) ₂ R ⁹ , and the C _3-10 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R ¹⁹ are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ . In one variation, R ¹⁹ is a 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ ; or a 3-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^10. In one variation, R ¹⁹ is a C _3-10 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ ; or a phenyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^10. In another variation, R ¹⁹ is cyano, -OR ⁷ , -NR ^8a R ^8b , or -S(O) ₂ R ^9. In another variation, R ¹⁹ is -OCH ₃ , -NH ₂ , or -S(O) ₂ CH ₃ .

からなる群から選択され、波線は親構造への結合点を表す。 In some of these embodiments, R ¹⁶ is

where the wavy line represents the point of attachment to the parent structure.

In some embodiments, R ¹⁵ is -NR ¹⁷ R ¹⁸ , where R ¹⁷ is hydrogen or C _1-6 alkyl and R ¹⁸ is a 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; a C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; or a C _1-6 alkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; or R ¹⁷ and R ¹⁸ , together with the nitrogen atom to which they are attached, form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ .

式中、
Ｒ^１７は、水素又はＣ_１－６アルキルであり、
Ｒ^１８は、Ｒ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換された３～１４員のヘテロシクリル；Ｒ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換されたＣ_３－１０シクロアルキル；若しくはＲ^１０から独立して選択される１、２、３、４若しくは５個の置換基で置換されたＣ_１－６アルキルでいるか、
又は、Ｒ^１７及びＲ^１８は、それらが結合する窒素原子と共に、Ｒ^１０から独立して選択される１、２、３、４、又は５個の置換基で任意に置換された４～１２員のヘテロシクリルを形成し、かつ
Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^１０は、式（Ｉ）、又は本明細書で詳述する変形について定義されるとおりである、
の化合物、又はその塩（例えば薬学的に許容され得る塩）を提供する。
いくつかの実施形態において、化合物は式（ＩＢ）の化合物、又はその塩（例えば、薬学的に許容され得る塩）であり、但し、化合物は、表１Ｘにおける化合物番号２ｘ～１４ｘ及び２５ｘ～１６０ｘ並びにその塩以外である。いくつかの実施形態において、化合物は式（ＩＢ）の化合物、又はその塩（例えば、薬学的に許容され得る塩）であり、但し、化合物は、表１Ｘにおける化合物番号２ｘ～１４ｘ及びその塩以外である。いくつかの実施形態において、化合物は式（ＩＢ）の化合物、又はその塩（例えば、薬学的に許容され得る塩）であり、但し、化合物は、表１Ｘにおける化合物番号２５ｘ～１６０ｘ及びその塩以外である。いくつかの実施形態において、Ｒ^１７は水素又はＣ_１－６アルキルであり、かつＲ^１８は、任意に置換されたピペリジニル及び任意に置換されたピペラジニル以外である。いくつかの実施形態において、Ｒ^１７は水素又はＣ_１－６アルキルであり、かつＲ^１８は、任意に置換されたピペリジニル（例えば、１－アルキルピペリジン－４－イル）以外である。いくつかの実施形態において、Ｒ^４は、任意に置換された５～６員の単環式ヘテロアリール（ｈｅｔｅｏａｒｙｌ）以外である。 In one embodiment, the compound of formula (IB)

In the formula,
R ¹⁷ is hydrogen or C _1-6 alkyl;
R ¹⁸ is a 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; a C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; or a C _1-6 alkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
or R ¹⁷ and R ¹⁸ , together with the nitrogen atom to which they are attached, form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; and R ¹ , R ³ , R ⁴ , R ⁵ and R ¹⁰ are as defined for formula (I), or any of the variations detailed herein;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).
In some embodiments, the compound is a compound of formula (IB), or a salt thereof (e.g., a pharma- ceutically acceptable salt), with the proviso that the compound is other than compound numbers 2x to 14x and 25x to 160x in Table 1X and salts thereof. In some embodiments, the compound is a compound of formula (IB), or a salt thereof (e.g., a pharma- ceutically acceptable salt), with the proviso that the compound is other than compound numbers 2x to 14x in Table 1X and salts thereof. In some embodiments, the compound is a compound of formula (IB), or a salt thereof (e.g., a pharma- ceutically acceptable salt), with the proviso that the compound is other than compound numbers 25x to 160x in Table 1X and salts thereof. In some embodiments, ^R17 is hydrogen or _C1-6 alkyl and ^R18 is other than optionally substituted piperidinyl and optionally substituted piperazinyl. In some embodiments, R ¹⁷ is hydrogen or C _1-6 alkyl and R ¹⁸ is other than optionally substituted piperidinyl (e.g., 1-alkylpiperidin-4-yl). In some embodiments, R ⁴ is other than an optionally substituted 5-6 membered monocyclic heteoaryl.

In some embodiments, the compound is a compound of Formula (I) or (IB) where R ¹⁷ is hydrogen or C _1-6 alkyl, or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof. In some of these embodiments, R ¹⁷ is hydrogen.

In some embodiments, the compound is a compound of Formula (I) or (IB), or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof, wherein R ¹⁸ is 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; or C _1-6 alkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ .

からなる群から選択され、波線は親構造への結合点を表す。 In one variation, R ¹⁸ is a 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^10. In some of these embodiments, R ¹⁸ is

where the wavy line represents the point of attachment to the parent structure.

からなる群から選択され、波線は親構造への結合点を表す。 In some embodiments, R ¹⁸ is a C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In some of these embodiments, R ¹⁸ is

where the wavy line represents the point of attachment to the parent structure.

In some embodiments, R ¹⁸ is C _1-6 haloalkyl or -(C _1-6 alkylene)-R ¹⁹ , and R ¹⁹ is _3-10 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, cyano, -OR ⁷ , -NR ^8a R ^8b , or -S(O) ₂ R ⁹ , and the C _3-10 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R ¹⁹ are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In some of these embodiments, R ¹⁹ is 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ . In some embodiments, R ¹⁹ is a C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ^10. In one variation, R ¹⁹ is an optionally substituted pyrazolyl (e.g., 1-methylpyrazol-4-yl), cyclopropyl, or cyano.

からなる群から選択され、波線は親構造への結合点を表す。 In some embodiments, R ¹⁸ is

where the wavy line represents the point of attachment to the parent structure.

In some embodiments, the compound is a compound of Formula (I) or (IB), or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof, wherein R ¹⁷ and R ¹⁸ , together with the nitrogen atom to which they are attached, form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In one variation, 4-12 membered heterocyclyl excludes piperazinyl. In one variation, 4-12 membered heterocyclyl excludes 4-methylpiperazin-1-yl and 1-oxotetrahydro-pyrrolo[1,2-c]imidazol-2-yl.

In some embodiments, R ¹⁵ is D.

式中、
Ｄは、

であり、式中、波線は親構造への結合点を表し、
Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４は、独立して水素又はＲ^１０であり、任意にＲ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４のうちの２つは、それらが結合する炭素原子と共に、Ｒ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換されたＣ_３－８シクロアルキル又はＲ^１０から独立して選択される１、２、３、４若しくは５個の置換基で任意に置換された３～１０員のヘテロシクリルを形成し、但し、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４のうちの少なくとも１つは水素以外であり、
Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^１０は、式（Ｉ）、又は本明細書で詳述する変形について定義されるとおりである、
の化合物、又はその塩（例えば薬学的に許容され得る塩）を提供する。
いくつかの実施形態において、化合物は、式（ＩＣ）の化合物、又はその塩（例えば、薬学的に許容され得る塩）であり、但し、化合物は、表１Ｘにおける化合物番号１５ｘ～２４ｘ及びその塩以外である。いくつかの実施形態において、Ｄは１－フルオロシクロプロピル、２－フェニルシクロプロピル及び２，２，３，３－テトラメチルシクロプロピルを除外する。いくつかの実施形態において、Ｒ^３０はフルオロ以外である。いくつかの実施形態において、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４のうちの少なくとも１つは、Ｒ^１１から独立して選択される１、２、３又は４個の置換基で任意に置換された５～１４員のヘテロアリールである。 In one embodiment, the compound of formula (IC)

In the formula,
D is

where the wavy line represents the point of attachment to the parent structure;
R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ are independently hydrogen or R ¹⁰ , and optionally two of R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ together with the carbon atom to which they are attached form a C _3-8 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ or a 3-10 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ , with the proviso that at least one of R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ is other than hydrogen;
R ¹ , R ³ , R ⁴ , R ⁵ and R ¹⁰ are as defined for formula (I), or any of the variations detailed herein;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).
In some embodiments, the compound is a compound of formula (IC), or a salt thereof (e.g., a pharma- ceutically acceptable salt), with the proviso that the compound is other than compound numbers 15x to 24x in Table 1X and salts thereof. In some embodiments, D excludes 1-fluorocyclopropyl, 2-phenylcyclopropyl, and 2,2,3,3-tetramethylcyclopropyl. In some embodiments, ^R30 is other than fluoro. In some embodiments, at least one of ^R30 , ^R31 , ^R32 , ^R33 , and ^R34 is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from ^R11 .

In some embodiments, the compound is a compound of Formula (I) or (IC) where R ³⁰ is hydrogen, or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof. In some embodiments, R ³¹ is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^11. In some of these embodiments, R ³¹ is a 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^11. In one variation, R ³¹ is 1-methylpyrazol-4-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-4-yl, or imidazol-5-yl. In some embodiments, R ³² , R ³³ , and R ³⁴ are independently selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl, cyanomethyl, and dimethylaminomethyl. In some embodiments, each R ³² , R ³³ , and R ³⁴ is hydrogen.

である。 In some embodiments, D is

It is.

In some embodiments, the compound is of Formula (I), or variations thereof such as Formula (IA), (IB), and (IC), or a salt (e.g., a pharma- ceutically acceptable salt) thereof, wherein ^R4 is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ^R10 . In some embodiments, ^R4 is a 5-10 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ^R10 . In some embodiments, ^R4 is a 5 or 6 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ^R10 . In some embodiments, ^R4 is a 5 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ^R10 . In some embodiments, ^R4 is a 6 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ^R10 .

であり、
波線は親構造への結合点を表し、
Ｒ^４ａ、Ｒ^４ｂ、及びＲ^４ｃは、それぞれ独立して水素又はＲ^１０であるか、又は、２つのビシナルなＲ^{４（ａ－ｃ）}は、それらが結合する原子と共に、Ｒ^１０から独立して選択される１、２、３、若しくは４個の置換基で任意に置換された縮合５若しくは６員のヘテロアリール、若しくは、Ｒ^１０から独立して選択される１、２、３、若しくは４個の置換基で任意に置換された縮合５若しくは６員のヘテロシクリルを形成する。 In some embodiments, ^R4 is

and
The wavy lines represent the attachment points to the parent structure.
R ^4a , R ^4b , and R ^4c are each independently hydrogen or R ¹⁰ , or two vicinal R ^4(a-c) together with the atom to which they are attached form a fused 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ , or a fused 5- or 6-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ .

であり、
波線は親構造への結合点を表し、Ｒ^４ａ、Ｒ^４ｂ及びＲ^４ｃは、それぞれ独立して水素若しくはＲ^１０であるか、又は２つのビシナルなＲ^{４（ａ－ｃ）}は、それらが結合する原子と共に、Ｒ^１０から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合５～１０員のヘテロシクリル若しくはＲ^１０から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合Ｃ_５－８シクロアルキルを形成する。 In some embodiments, ^R4 is

and
The wavy line represents the point of attachment to the parent structure and R ^4a , R ^4b and R ^4c are each independently hydrogen or R ¹⁰ , or two vicinal R ^4(a-c) together with the atom to which they are attached form a fused 5-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ or a fused C _5-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹⁰ .

からなる群から選択される。 In some of these embodiments, ^R4 is

is selected from the group consisting of:

であり、
Ｒ^４ａはハロゲン、Ｃ_１－６アルキル又はＣ_３－６シクロアルキルであり；かつＲ^４ｂ及びＲ^４ｃは、それらが結合する原子と共に、Ｃ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合５～１０員のヘテロシクリル、又はＣ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合Ｃ_５－８シクロアルキルを形成する。 In some embodiments, ^R4 is

and
R ^4a is halogen, C _1-6 alkyl or C _3-6 cycloalkyl; and R ^4b and R ^4c together with the atom to which they are attached form a fused 5-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano, or a fused C _5-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano.

からなる群から選択される。 In some of these embodiments, ^R4 is

is selected from the group consisting of:

からなる群から選択される。 In some of these embodiments, ^R4 is

is selected from the group consisting of:

からなる群から選択される。 In some of these embodiments, ^R4 is

is selected from the group consisting of:

であり、かつ
Ｒ^４は、

からなる群から選択される。これらの実施形態のいくつかでは、Ｒ^４は、

からなる群から選択される。 It is intended and understood that each and every variation of R ¹⁵ described for formula (I), or variations thereof, such as formula (IA), (IB) or (IC), may be combined with each and every variation of R ⁴ described for formula (I), (IA), (IB) or (IC), just as if each and every combination were specifically and individually set forth. For example, in some embodiments, R ¹⁵ is (a), (b) or (c):
(a) -OR ¹⁶ [wherein R ¹⁶ is (i), (ii), (iii), (iv) or (v):
(i) a 4-10 membered heterocyclyl having 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, and optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ ;
(ii) C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
(iii) neopentyl,
(iv) C _1-6 haloalkyl, or (v) -(C _1-6 alkylene)-R ¹⁹ , wherein R ¹⁹ is 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; C _3-10 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; phenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹⁰ ; cyano, -OR ⁷ , -NR ^8a R ^8b , or -S(O) ₂ R ⁹ ,
(b) -NR ¹⁷ R ¹⁸ , where R ¹⁷ is hydrogen and R ¹⁸ is 3 to 14 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ , C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ ; C _1-6 haloalkyl, or -(C _1-6 alkylene)-R ¹⁹ , where R ¹⁹ is optionally substituted pyrazolyl (e.g. 1-methylpyrazol-4-yl), cyclopropyl, or cyano; or (c)

and ^R4 is

In some of these embodiments, ^R4 is selected from the group consisting of:

is selected from the group consisting of:

In some embodiments, the compound is of Formula (I), or variations thereof such as Formula (IA), (IB), and (IC), or a salt (e.g., a pharma- ceutically acceptable salt) thereof, where ^R1 is hydrogen, halogen, hydroxyl, _C1-6 alkyl, _C1-6 haloalkyl, _C3-4 cycloalkyl, -O( _C1-6 alkyl), or -O( _C1-6 haloalkyl). In some embodiments, ^R1 is hydrogen, fluoro, chloro, _C3-4 cycloalkyl, _C1-6 alkyl, _C1-6 haloalkyl, -O( _C1-6 alkyl), or -O( _C1-6 haloalkyl). In some embodiments, ^R1 is hydrogen or halogen. In one variation, ^R1 is hydrogen, fluoro, chloro, or _C1-6 alkyl (e.g., methyl). In another variation, ^R1 is hydrogen, fluoro, or methyl. In another variation, ^R1 is hydrogen or fluoro. In another variation, ^R1 is hydrogen.

In some embodiments, the compound is of Formula (I) or variations thereof, such as Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharma- ceutically acceptable salt), where ^R3 is hydrogen, halogen, cyano, _C1-6 alkyl, _C3-8 cycloalkyl, 3-14 membered heterocyclyl, or ^-OR7 , where the C1-6 alkyl, _C3-8 cycloalkyl, and 3-14 membered _heterocyclyl of ^R3 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ^R10 . In some embodiments, ^R3 is hydrogen, fluoro, chloro, cyano _, hydroxyl, _C3-4 cycloalkyl, C1-6 alkyl, _C1-6 haloalkyl, -O( _C1-6 alkyl), or -O( _C1-6 haloalkyl). In one variation, R ³ is hydrogen, fluoro, cyano, or C _1-6 alkyl (eg, methyl). In another variation, R ³ is hydrogen or fluoro. In another variation, R ³ is hydrogen.

In some embodiments, the compound is of Formula (I), or variations thereof such as Formula (IA), (IB) and (IC), or a salt thereof (e.g., a pharma- ceutically acceptable salt), wherein ^R5 is hydrogen, halogen, cyano, _C1-6 alkyl, _C2-6 alkenyl, _{C2-6 alkynyl, C3-8 cycloalkyl} , _C6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, -C(O) ^R6 , -C(O ^{) OR7} , -C(O) ^{NR8aR8b ,} -OR7 _{, -OC} (O) ^R6 , -OC(O ^{) NR8aR8b} , ^-SR7 , -S(O) ^R9 , -S(O) ^{2R9 ,} -S(O) ^2NR8aR8b , -P(O) ^R9aR and R ⁵ is C ^{1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl , C 3-8} _cycloalkyl ^{, C} _6-14 aryl, ^5- _{to 14-} membered heteroaryl and 3- to 14-membered ^heterocyclyl , each of which is optionally substituted by 1 _, ² , ₃ , ₄ or ^{5 substituents independently selected from R 10 .} In some embodiments, R ⁵ is hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3-14 membered heterocyclyl, -OR ⁷ , -NR ^8a R ^8b , or -N(R ⁸ )C(O)R ⁶ , wherein the C _1-6 alkyl, C _3-8 cycloalkyl, and 3-14 membered heterocyclyl of R ⁵ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In some embodiments, R ⁵ is hydrogen, fluoro, chloro, cyano, hydroxyl, C _3-4 cycloalkyl C _1-6 alkyl, C _1-6 haloalkyl, -O(C _1-6 alkyl), or -O(C _1-6 haloalkyl). In one variation, R ⁵ is hydrogen, fluoro, cyano, or C _1-6 alkyl. In another variation, R ⁵ is hydrogen, fluoro, or chloro. In another variation, ^R5 is hydrogen.In another variation, ^R5 is fluoro.

からなる群から選択される。これらの実施形態のいくつかにおいて、Ｒ^４は、

からなる群から選択される。 It is intended and understood that any variation of R ¹ , R ³ , and R ⁵ described in formula (I), (IA), (IB), or (IC) can be combined, as if any combination were specifically and individually described. For example, in some embodiments, R ¹ is hydrogen or halogen, R ³ is hydrogen, and R ⁵ is hydrogen, fluoro, or chloro. In one variation, R ¹ is hydrogen or chloro, R ³ is hydrogen, and R ⁵ is fluoro.
It is further intended and understood that each and every variation or combination of R ¹⁵ and R ⁴ described for formula (I) may be combined with each and every variation of R ¹ , R ³ and R ⁵ described for formula (I), or formula (IA), (IB) or (IC), as if each and every combination were specifically and individually described. For example, in some embodiments, R ¹ is hydrogen or chloro, R 3 ^is hydrogen, R ⁵ is fluoro, and R ⁴ is as detailed herein for formula (I), or variations thereof, such as formula (IA), (IB) and (IC). In some embodiments of a compound of formula (I), or a salt thereof (e.g., a pharma- ceutically acceptable salt), R ¹ is hydrogen or chloro, R ² is (a), (b) or (c) as detailed above, R ³ is hydrogen, R ⁵ is fluoro, and R ⁴ is

In some of these embodiments, ^R4 is selected from the group consisting of:

is selected from the group consisting of:

In some embodiments, the compound is of formula (I) or a variation thereof, where applicable, such as formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharma- ceutically acceptable salt), wherein ^each R is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, wherein the C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, _5-14 membered heteroaryl, and 3-12 membered heterocyclyl of R is each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ . In one variation, R ⁶ is C _1-6 alkyl, C _3-8 cycloalkyl, or 3-12 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, and 3-12 membered heterocyclyl of R ⁶ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In one variation, R ⁶ is C _1-6 alkyl (e.g., methyl). In one variation, R ⁶ is 3-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ .

In some embodiments of compounds of Formula (I) or variations thereof, such as Formulas (IA), (IB), and (IC), where applicable, or salts thereof (e.g., pharma-ceutically acceptable salts), each R ⁷ is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-12 membered heterocyclyl of R ⁷ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ^10. In one variation, R ⁷ is hydrogen, C _1-6 alkyl optionally substituted with R ^10. In one variation, R ⁷ is C _1-6 alkyl. In one variation, R ⁷ is 3-12 membered heterocyclyl.

In some embodiments of compounds of Formula (I), or variations thereof, such as, where applicable, Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharma- ceutically acceptable salt), R ⁸ is independently hydrogen or C _1-6 alkyl; each R ^8a and R ^8b is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-12 membered heterocyclyl of R ^8a and R ^8b are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ , or R ^8a and R ^8b , together with the nitrogen atom to which they are attached, are R ^10. In one variation, R ⁸ is hydrogen or C _1-6 alkyl (e.g., methyl). In one variation, each R ^8a and R ^8b is independently hydrogen or C _1-6 alkyl. In one variation, each R ^8a and R ^8b is hydrogen. In one variation, R ^8a and R ^8b together with the nitrogen atom to which they are attached form a 5-7 membered heterocyclyl optionally substituted with R ¹⁰ .

In some embodiments of compounds of formula (I) or variations thereof, such as formulas (IA), (IB), and (IC), where applicable, or salts thereof (e.g., pharma- ceutically acceptable salts), each ^R9 is independently _C1-6 alkyl, _C3-8 cycloalkyl, _C6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, wherein the _C1-6 alkyl, _C3-8 cycloalkyl, _C6-10 aryl, 5-14 membered heteroaryl, and 3-12 membered heterocyclyl of ^R9 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ^R10 . In one variation, ^R9 is _C1-6 alkyl optionally substituted with ^R10 , or _C6-10 aryl optionally substituted with ^R10 . In one variation, ^R9 is hydrogen or _C1-6 alkyl (e.g., methyl).

In some embodiments of compounds of formula (I) or variations thereof, such as formulas (IA), (IB), and (IC), where applicable, or salts thereof (e.g., pharma- ceutically acceptable salts), each R ¹⁰ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, halogen, cyano, —C(O)R ^a , —C(O)OR ^b , —C(O)NR ^c R ^d , —OR ^b , —OC(O)R ^a , —OC(O)NR ^c R ^d , —SR ^b , —S(O)R ^e , —S(O) ₂ R ^e , —S(O)(═NH)R ^e , —S(O) ₂ NR ^c R ^d , -NR ^c R ^d , -N(R ^f )C(O)R ^a , -N(R ^f )C(O)OR ^b , -N(R ^f )C(O)NR ^c R ^d , -N(R ^f )S(O) ₂ R ^e , or -N(R ^f )S(O) ₂ NR ^c R ^d , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R ¹⁰ are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ .

In one variation, R ¹⁰ is independently oxo, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, halogen, cyano, -C(O)R ^a , -C(O)NR ^c R ^d , -OR ^b , -S(O) ₂ R ^e , -S(O) ₂ NR ^c R ^d , -NR ^c R ^d ; and the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R ¹⁰ are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ .

In one variation, R ¹⁰ is independently oxo; C _1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ; 5-10 membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ; halogen, -OR ^b , -S(O)(═NH)R ^e , -NR ^c R ^d , -N(R ^f )C(O)R ^a , or -N(R ^f )S(O) ₂ NR ^c R ^d .

In one variation, R ¹⁰ is independently oxo, halogen, cyano, C _1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ , or —OR ^b .

In one variation, R ¹⁰ is independently -NR ^c R ^d , -N(R ^f )C(O)R ^a , -N(R ^f )C(O)OR ^b , -N(R ^f )C(O)NR ^c R ^d , -N(R ^f )S(O) ₂ R ^e , or -N(R ^f )S(O) ₂ NR ^c R ^d .

In one variation, R ¹⁰ is independently oxo, —OR ^b , —OC(O)R ^a , —OC(O)NR ^c R ^d , —SR ^b , —S(O)R ^e , —S(O) ₂ R ^e , —S(O)(═NH)R ^e , or —S(O) ₂ NR ^c R ^d .

In one variation, R ¹⁰ is independently C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, halogen, cyano, -C(O)R ^a , -C(O)OR ^b , -C(O)NR ^c R ^d , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R ¹⁰ are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ .

In one variation, each R ¹⁰ is independently a C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, each optionally substituted with 1, 2, ₃ or 4 substituents independently selected from R ¹¹ .

In one variation, R ¹⁰ is a C _1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^11. In one variation, R ¹⁰ is a 3-12 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ .

In one variation, R ¹⁰ is halogen, cyano, —NR ^c R ^d , —C(O)NR ^c R ^d , —OR ^b , —S(O) ₂ R ^e , C _1-6 haloalkyl, —(C _1-6 alkylene)-OH, or —(C _1-6 alkylene)-OH.

In one variation, R ¹⁰ is hydroxyl, cyano, halogen, —CHF ₂ , —CF ₃ , —NH ₂ , —NH(C _1-6 alkyl), —N(C _1-6 alkyl) ₂ , —O(C _1-6 alkyl), —SO ₂ (C _1-6 alkyl), —S(O) ₂ NR ^c R ^d , —C(O)NR ^c R ^d , or —N(R ^f )C(O)R ^a .

In some embodiments, each R ^a is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^a are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^11. In one variation, R ^a is independently hydrogen or C _1-6 alkyl. In one variation, R ^a is hydrogen. In one variation, R ^a is C _1-6 alkyl (e.g., methyl).

In some embodiments, each R ^b is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^b are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^11. In one variation, R ^b is independently hydrogen or C _1-6 alkyl. In one variation, R ^b is hydrogen. In one variation, R ^b is C _1-6 alkyl (e.g., methyl).

In some embodiments, each R ^c and R ^d is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^c and R ^d are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ; or R ^c and R ^d together with the nitrogen atom to which they are attached form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^11. In one variation, each R ^c and R ^d is independently hydrogen or C _1-6 alkyl. In one variation, one of R ^c and R ^d is hydrogen and the other one of R ^c and R ^d is C _1-6 alkyl. In one variation, each R ^c and R ^d is hydrogen. In one variation, each R ^c and R ^d is independently C _1-6 alkyl.

In some embodiments, each R ^e is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^e are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^11. In one variation, R ^e is independently C _1-6 alkyl (e.g., methyl).

In some embodiments, each R ^f is independently hydrogen or C _1-6 alkyl. In one variation, R ^f is hydrogen.

In some embodiments, each R ¹¹ is independently selected from oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, halogen, cyano, —C(O)R ^a1 , —C(O)OR ^b1 , —C(O)NR ^c1 R ^d1 , —OR ^b1 , —OC(O)R ^a1 , —OC(O)NR ^c1 R ^d1 , —SR ^b1 , —S(O)R ^e1 , —S(O) ₂ R ^e1 , —S(O) ₂ NR ^c1 R ^d1 , —NR ^c1 R ^d1 , —N(R ^f1 )C(O)R ^a1 , —N(R ^f1 )C(O)OR ^b1 , -N(R ^f1 )C(O)NR ^c1 R ^d1 , -N(R ^f1 )S(O) ₂ R ^e1 , or -N(R ^f1 )S(O) ₂ NR ^c1 R ^d1 , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 alkyl, 5-14 membered heteroaryl, and 3-14 membered heterocyclyl of R ¹¹ are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² .

In one variation, each R ¹¹ is independently oxo, C _1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² , or —OR ^b1 .

In one variation, each R ¹¹ is independently oxo, C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, halogen, cyano, or -OR ^b1 , wherein the C _1-6 alkyl, C _3-6 cycloalkyl, and 3- to 14-membered heterocyclyl of R ¹¹ are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² .

In one variation, R ¹¹ is a C _1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^12. In one variation, R ¹¹ is a 3-8 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² .

In one variation, R ¹¹ is halogen, cyano, —NR ^c1 R ^d1 , —C(O)NR ^c1 R ^d1 , —OR ^b1 , —S(O) ₂ R ^e1 , C _1-6 haloalkyl, —(C _1-6 alkylene)-OH, or —(C _1-6 alkylene)-OH.

In one variation, R ¹¹ is hydroxyl, cyano, halogen, —CHF ₂ , —CF ₃ , —NH ₂ , —NH(C _1-6 alkyl), —N(C _1-6 alkyl) ₂ , —O(C _1-6 alkyl), —SO ₂ (C _1-6 alkyl), —S(O) ₂ NR ^c1 R ^d1 , —C(O)NR ^c1 R ^d1 , or —N(R ^f1 )C(O)R ^a1 .

In one variation, R ¹¹ is halogen, cyano, —O(C _1-6 alkyl), —O(C _1-6 alkylene)-NH ₂ , or —(C _1-6 alkylene)-OH.

In some embodiments, each R ^a1 is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl of R ^a1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^12. In one variation, R ^a1 is independently hydrogen or C _1-6 alkyl (e.g., methyl).

In some embodiments, each R ^b1 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl of R ^b1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^12. In one variation, R ^b1 is independently hydrogen or C _1-6 alkyl. In one variation, R ^b1 is hydrogen. In one variation, R ^b1 is C _1-6 alkyl (e.g., methyl).

In some embodiments, each R ^c1 and R ^d1 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, where the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl of R ^c1 and R ^d1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² , or R ^c1 and R ^d1 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^12. In one variation, each R ^c1 and R ^d1 is independently hydrogen or C _1-6 alkyl.

In some embodiments, each R ^e1 is independently C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl of R ^e1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^12. In one variation, R ^e1 is independently C _1-6 alkyl.

In some embodiments, each R ^{f1 is} independently hydrogen or C _1-6 alkyl.

In some embodiments, each R ¹² is independently oxo, C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, halogen, cyano, —C(O)R ^a2 , —C(O)OR ^b2 , —C(O)NR ^c2 R ^d2 , —OR ^b2 , —OC(O)R ^a2 , —OC(O)NR ^c2 R ^d2 , —S(O) ₂ R ^e2 , —S(O) ₂ NR ^c2 R ^d2 , —NR ^c2 R ^d2 , —N(R ^f2 )C(O)R ^a2 , —N(R ^f2 )C(O)OR ^b2 , —N(R ^f2 )C(O)NR ^c2 R ^d2 , -N( ^Rf2 )S( _O ) _2Re2 , or -N( ^Rf2 )S( ^{O)2NRc2Rd2 , wherein} the _C1-6 alkyl, _C3-6 cycloalkyl, _C6 aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of ^R12 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from ^R13 ;

In one variation, each R ¹² is independently oxo, halogen, cyano, -OR ^b2 , or C _1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^13. In one variation, each R ¹² is independently oxo, halogen, cyano, or hydroxyl.

In one variation, R ¹² is a C _1-6 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ .

In one variation, R ¹² is oxo, hydroxyl, C _1-6 alkyl, or —O(C _1-6 alkyl).

In some embodiments, each R ^a2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of R ^a2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^13. In one variation, R ^a2 is independently hydrogen or C _1-6 alkyl.

In some embodiments, each R ^b2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, and 3-6 membered heterocyclyl of R ^b2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^13. In one variation, R ^b2 is hydrogen.

In some embodiments, each R ^c2 and R ^d2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3-8 membered heterocyclyl, where the C _1-6 alkyl, C _3-6 cycloalkyl, and 3-8 membered heterocyclyl of R ^c2 and R ^d2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ , or R ^c2 and R ^d2 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^13. In one variation, each R ^c2 and R ^d2 is independently hydrogen or C _1-6 alkyl.

In some embodiments, each R ^e2 is independently C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of R ^e2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^13. In one variation, R ^e2 is independently C _1-6 alkyl.

In some embodiments, each R ^f2 is independently hydrogen or C _1-6 alkyl. In one variation, R ^f2 is hydrogen.

In some embodiments, each R ¹³ is independently oxo, halogen, hydroxyl, --O(C _1-6 alkyl), cyano, C _1-6 alkyl, or C _1-6 haloalkyl.

In one variation, each R ¹³ is independently halogen, hydroxyl, —O(C _1-6 alkyl), cyano, or C _1-6 alkyl.

In one variation, R ¹³ is oxo, hydroxyl, C _1-6 alkyl, or —O(C _1-6 alkyl).

式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^１６は、式（Ｉ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を更に提供する。 Formula (IA):

wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ¹⁶ are as detailed herein for formula (I), or applicable variations thereof;
or a salt thereof (eg, a pharma- ceutically acceptable salt).

式中、Ｒ^１、Ｒ^４及びＲ^１６は、式（ＩＡ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を提供する。 In some embodiments, the compound of formula (IA-1):

wherein R ¹ , R ⁴ and R ¹⁶ are as detailed herein for formula (IA), or applicable variations thereof;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).

式中、Ｒ^４ａはＣ_１－６アルキルであり、Ｒ^４ｂ及びＲ^４ｃは、独立して水素若しくはＲ^１０であるか、又はＲ^４ｂ及びＲ^４ｃは、それらが結合する原子と共に、Ｃ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合５～１０員のヘテロシクリル、又はＣ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合Ｃ_５－８シクロアルキルを形成し、かつＲ^１、Ｒ^１０及びＲ^１６は、式（ＩＡ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を提供する。一変形において、Ｒ^１６は、Ｎ、Ｏ及びＳからなる群から独立して選択される１又は２個のヘテロ原子を有し、かつＲ^１０から独立して選択される１、２、３、４又は５個の置換基で任意に置換された５又は６員のヘテロシクリルであり、Ｒ^４ａはＣ_１－６アルキル（例えば、メチル）であり、かつＲ^４ｂ及びＲ^４ｃは、それらが結合する原子と共に、Ｃ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３又は４個の置換基で任意に置換された縮合６員のヘテロシクリルを形成する。 In some embodiments, the compound of formula (IA-2):

wherein R ^4a is C _1-6 alkyl; R ^4b and R ^4c are independently hydrogen or R ¹⁰ ; or R ^4b and R ^4c together with the atom to which they are attached form a fused 5-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; or a fused C _5-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; and R ¹ , R ¹⁰ and R ¹⁶ are as detailed herein for formula (IA), or applicable variations thereof.
or a salt (e.g., a pharma- ceutically acceptable salt) thereof. In one variation, R ¹⁶ is a 5- or 6-membered heterocyclyl having 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, and optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ , R ^4a is C _1-6 alkyl (e.g., methyl), and R ^4b and R ^4c together with the atom to which they are attached form a fused 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano.

式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^１７及びＲ^１８は、式（Ｉ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）も提供する。 Formula (IB):

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ¹⁷ and R ¹⁸ are as detailed herein for formula (I), or applicable variations thereof;
or a salt thereof (eg, a pharma- ceutically acceptable salt).

式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^１８は、式（ＩＢ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を提供する。 In some embodiments, the formula (IB-1):

wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ¹⁸ are as detailed herein for formula (IB), or applicable variations thereof;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).

式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^１８は、式（ＩＢ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を提供する。 In some embodiments, the formula (IB-2):

wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ¹⁸ are as detailed herein for formula (IB), or applicable variations thereof;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).

式中、Ｒ^４ａはＣ_１－６アルキルであり、Ｒ^４ｂ及びＲ^４ｃは、独立して水素若しくはＲ^１０であるか、又はＲ^４ｂ及びＲ^４ｃは、それらが結合する原子と共に、Ｃ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合５～１０員のヘテロシクリル、又はＣ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合Ｃ_５－８シクロアルキルを形成し、かつＲ^１、Ｒ^１０及びＲ^１８は、式（ＩＢ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を提供する。 In some embodiments, the formula (IB-3):

wherein R ^4a is C _1-6 alkyl; R ^4b and R ^4c are independently hydrogen or R ¹⁰ ; or R ^4b and R ^4c together with the atom to which they are attached form a fused 5-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; or a fused C _5-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; and R ¹ , R ¹⁰ and R ¹⁸ are as detailed herein for formula (IB), or applicable variations thereof.
or a salt thereof (e.g., a pharma- ceutically acceptable salt).

式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５及びＤは、式（Ｉ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）も提供する。 Formula (IC):

wherein R ¹ , R ³ , R ⁴ , R ⁵ and D are as detailed herein for formula (I), or applicable variations thereof;
or a salt thereof (eg, a pharma- ceutically acceptable salt).

式中、Ｒ^４ａはＣ_１－６アルキルであり、Ｒ^４ｂ及びＲ^４ｃは、独立して水素若しくはＲ^１０であるか、又はＲ^４ｂ及びＲ^４ｃは、それらが結合する原子と共に、Ｃ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合５～１０員のヘテロシクリル、又はＣ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合Ｃ_５－８シクロアルキルを形成し、かつＲ^１、Ｒ^３、Ｒ^５、Ｒ^１０、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４は、式（ＩＣ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を提供する。 In some embodiments, the compound of formula (IC-1):

wherein R ^4a is C _1-6 alkyl; R ^4b and R ^4c are independently hydrogen or R ¹⁰ ; or R ^4b and R ^4c together with the atom to which they are attached form a fused 5-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; or a fused C _5-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; and R ¹ , R ³ , R ⁵ , R ¹⁰ , R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ are as detailed herein for formula (IC), or applicable variations thereof;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).

式中、Ｒ^４ａはＣ_１－６アルキルであり、Ｒ^４ｂ及びＲ^４ｃは、独立して水素若しくはＲ^１０であるか、又はＲ^４ｂ及びＲ^４ｃは、それらが結合する原子と共に、Ｃ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合５～１０員のヘテロシクリル、又はＣ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合Ｃ_５－８シクロアルキルを形成し、かつＲ^１、Ｒ^１０、Ｒ^３０、Ｒ^３１、Ｒ^３２、Ｒ^３３及びＲ^３４は、式（ＩＣ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を提供する。 In some embodiments, the compound of formula (IC-2):

wherein R ^4a is C _1-6 alkyl; R ^4b and R ^4c are independently hydrogen or R ¹⁰ ; or R ^4b and R ^4c together with the atom to which they are attached form a fused 5-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; or a fused C _5-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; and R ¹ , R ¹⁰ , R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ are as detailed herein for formula (IC), or applicable variations thereof;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).

式中、Ｒ^４ａはＣ_１－６アルキルであり、Ｒ^４ｂ及びＲ^４ｃは、独立して水素若しくはＲ^１０であるか、又はＲ^４ｂ及びＲ^４ｃは、それらが結合する原子と共に、Ｃ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合５～１０員のヘテロシクリル、又はＣ_１－６アルキル、ヒドロキシル、ハロゲン及びシアノからなる群から独立して選択される１、２、３若しくは４個の置換基で任意に置換された縮合Ｃ_５－８シクロアルキルを形成し、Ｒ^３０は、Ｒ^１０から独立して選択される１、２、３、４又は５個の置換基で任意に置換された５～１４員のヘテロアリールであり、ｎは０、１、２、３又は４であり、各Ｒ^３１は、存在する場合、Ｒ^１０から独立して選択され、かつＲ^１、Ｒ^１０、Ｒ^３１及びＲ^３３は、式（ＩＣ）、又はその適用可能な変形について本明細書に詳述されるとおりである、
の化合物、又はその塩（例えば、薬学的に許容され得る塩）を提供する。 In some embodiments, the compound of formula (IC-3):

wherein R ^4a is C _1-6 alkyl; R ^4b and R ^4c are independently hydrogen or R ¹⁰ ; or R ^4b and R ^4c together with the atom to which they are attached form a fused 5-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; or a fused C _5-8 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C _1-6 alkyl, hydroxyl, halogen and cyano; R ³⁰ is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ ; n is 0, 1, 2, 3 or 4; each R ³¹ , if present, is independently selected from R ¹⁰ ; and R ¹ , R ¹⁰ , R ³¹ and R ³³ is as detailed herein for formula (IC), or applicable variations thereof;
or a salt thereof (e.g., a pharma- ceutically acceptable salt).

Representative compounds are listed in Table 1. It is understood that the individual enantiomers and diastereomers are included in the table below by compound number and compound name, and their corresponding structures can be readily determined therefrom. In some cases, the enantiomers and diastereomers are distinguished by their respective properties, such as retention time on chiral HPLC, or biological activity, and the absolute stereoconfiguration of the chiral centers is arbitrarily assigned.

In some embodiments, a compound selected from compound numbers 101-142, 201-207, and 301-302 in Table 1, or a salt thereof (e.g., a pharma- ceutically acceptable salt) is provided. In some embodiments, the compound is compound number 101, 102, 103, 104, 105, 106, 106a, 106b, 107, 107a, 107b, 108, 108a, 108b, 109, 109a, 109b, 110, 110a, 110b, 111, 112, 113, 114, 114a, 114b, 115, 116, 116a, 116b, 117, 118, 119, 120, 121, 122, 122a, 122b, 123, 123a, 123b, 124, 125, 126, 126a, 126b, 127, 127a , 127b, 128, 128a, 128b, 129, 129, 130, 131, 132, 133, 134, 134a, 134b, 135, 135a, 135b, 136, 136a, 136b, 137, 138, 139, 140, 141, 142, 201, 201a, 201b, 202, 203, 203a, 203b, 204, 205, 206, 206a, 206b, 207, 301, 301a, 301b, 301c, 301d, 302, 302a and 302b, or a salt thereof (e.g., a pharma- ceutically acceptable salt).

In some embodiments, a compound selected from compound numbers 101 to 142 in Table 1, or a salt thereof (e.g., a pharma- ceutically acceptable salt) is provided. In some embodiments, the compound is compound numbers 101, 102, 103, 104, 105, 106, 106a, 106b, 107, 107a, 107b, 108, 108a, 108b, 109, 109a, 109b, 110, 110a, 110b, 111, 112, 113, 114, 114a, 114b, 115, 116, 116a, 116b, 117, 118, 119, 120, 121, 122, 122a, 1 22b, 123, 123a, 123b, 124, 125, 126, 126a, 126b, 127, 127a, 127b, 128, 128a, 128b, 129, 129, 130, 131, 132, 133, 134, 134a, 134b, 135, 135a, 135b, 136, 136a, 136b, 137, 138, 139, 140, 141, and 142, or a salt thereof (e.g., a pharma- ceutically acceptable salt).

In some aspects, a compound or a salt thereof (e.g., a pharma- ceutically acceptable salt) is provided that is selected from compound numbers 201-207 in Table 1. In some embodiments, the compound is selected from compound numbers 201, 201a, 201b, 202, 203, 203a, 203b, 204, 205, 206, 206a, 206b, and 207 in Table 1, or a salt thereof (e.g., a pharma- ceutically acceptable salt).

In some embodiments, a compound selected from compound numbers 301-302 in Table 1, or a salt thereof (e.g., a pharma- ceutically acceptable salt) is provided. In some embodiments, the compound is selected from compound numbers 301, 301a, 301b, 301c, 301d, 302, 302a, and 302b in Table 1, or a salt thereof (e.g., a pharma- ceutically acceptable salt).

The compounds of formula (I) or salts thereof described herein can exist in stereoisomeric forms (e.g., containing one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers), as well as mixtures thereof, are within the scope of the subject matter disclosed herein. Similarly, it is understood that the compounds of formula (I) or salts can exist in tautomeric forms other than those shown in the formula, which are also within the scope of the subject matter disclosed herein. The subject matter disclosed herein should be understood to include combinations and subsets of the specific groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers, and purified enantiomers, or enantiomerically/diastereically enriched mixtures. The subject matter disclosed herein should be understood to include combinations and subsets of the specific groups defined herein.

The subject matter disclosed herein also includes isotopically labeled forms of the compounds described herein, with respect to the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds described herein and their pharma- ceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ^2H , ^3H , ^11C , ^13C , ^14C , ^15N , ^17O , ^18O , ^31P , ^32P , 35S, ^18F , ^36Cl , ^123I , and ^{125I .}

The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharma- ceutically acceptable salts of compounds of formula (I). Metabolites of compounds of formula (I) include compounds made by a process comprising contacting a compound of formula (I) with a mammal for a time sufficient to yield a metabolic product thereof.

When the compound of formula (I) is a base, the desired pharma- ceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.), or an organic acid (e.g., acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids (e.g., glucuronic acid or galacturonic acid), alpha hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc.).

When the compound of formula (I) is an acid, the desired pharma- ceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (such as glycine and arginine), ammonia, primary, secondary and tertiary amines, and cyclic amines (such as piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The compounds of formula (I) can be in the form of "prodrugs", which include compounds having moieties capable of being metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to the active drug. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). Prodrugs can be prepared during the final isolation and purification of the compound, or in situ by separately reacting the purified compound in its free acid form or at the hydroxyl with a suitable esterifying agent. The hydroxyl group can be converted to an ester by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkylamino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloxymethyl esters), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Prodrugs that are converted to active forms by other in vivo mechanisms are also included. In some embodiments, the compounds of the present invention are prodrugs having any of the formulas herein.

Compounds of formula (I) may be prepared by the general synthetic methods described herein, and in addition to the procedures described in the Examples, by methods known in the art.
General synthesis method

Compounds of formula (I) can be prepared by the procedures in the Examples and generally by Schemes 1, 2 and 3, where the R groups are as described in formula (I) or are precursors thereof.

Scheme 1 shows a general synthetic scheme for preparing compounds of formula (I) from compounds of formula 2 which in turn can be prepared from compounds of formula 1, where ^X4 is a halogen (e.g., Cl, Br, or I), where ^R1 , ^R3 , ^R4 , ^R5 , and ^R15 are as detailed herein. Introduction of R ⁴ can be achieved by Suzuki coupling of compounds of formula 1 with the corresponding boronic acid or boronic pinacol ester of formula R ⁴ -B(OR) _{2 ,} where R is H, optionally substituted C _1-6 alkyl, or the two OR groups together with the boron atom to which they are attached form a ring (e.g. boronic pinacol), using a _palladium based catalyst (e.g. Pd(dppf)Cl 2 or (Ph 3 P) ₄ Pd) in the presence of a base (e.g. sodium carbonate or potassium acetate) in a solvent (e.g. 1,4-dioxane and water, or acetonitrile and water). The 3-amino group of compounds of formula 2 may be acylated with an acylating agent of formula R ¹⁵ -C(O)-X ² , where X ² is a leaving group such as Cl, Br or I, in the presence of a base (e.g. pyridine) and a solvent (e.g. dichloromethane). In the case of carbamates (R ¹⁵ is -OR ¹⁶ ), the compound of formula R ¹⁵ -C(O)-X ² may be a chloroformate of formula R ¹⁶ -OC(O)Cl. In the case of ureas (R ¹⁵ is -NR ¹⁷ R ¹⁸ ), the compound of formula 2 is reacted with a carbonylating agent (e.g., phosgene or an equivalent such as triphosgene) and an amine of formula HNR ¹⁷ R ¹⁸ in the presence of a base (e.g., pyridine) and a solvent (e.g., dichloromethane) to form a compound of formula (I). In the case of cyclopropanecarboxamides (R ¹⁵ is a substituted cyclopropyl group), the acylating agent (or equivalent) of formula "R ¹⁵ -C(O)-X ² " may be a substituted cyclopropanecarbonyl halide or a substituted cyclopropanecarboxylic acid activated by an activating agent.

Alternatively, the compound of formula 2 can be converted to the corresponding phenyl carbamate of formula 2a (R' is H or nitro, e.g., 4-nitro) by reaction with an optionally substituted phenyl chloroformate, which can then be reacted with an alcohol (R ¹⁶ -OH) or amine (HNR ¹⁷ R ¹⁸ ) in the presence of a base (e.g., pyridine) and a solvent (e.g., dichloromethane) to form a compound of formula (I) (R ¹⁵ is -OR ¹⁶ or -NR ¹⁷ R ¹⁸ , respectively). Optionally, any active functional groups are protected during processing, and the protecting groups are removed to form a compound of formula (I). When one or more of R ¹ , R ³ , and R ⁵ of the compound of formula 1 are halogens, X ⁴ is a more reactive halogen for Suzuki coupling. For example, when R ¹ of the compound of formula 1 is Cl, X ⁴ is Br or I.

式（Ｉ）：
［式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５及びＲ^１５は、本明細書で詳述するとおりである］の化合物、又はその塩の作製方法であって、式２：

［式中、Ｒ^１、Ｒ^３、Ｒ^４及びＲ^５は、式（Ｉ）、任意にその保護形態で定義されるとおりである］の化合物、又はその塩を、式Ｒ^１５－Ｃ（Ｏ）－Ｘ^２［式中、Ｘ^２はＣｌ、Ｂｒ、又はＩである］の化合物と塩基（例えば、ピリジン）及び溶媒（例えば、ジクロロメタン）の存在下で反応させることを含む、方法を提供する。

Formula (I):
wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ¹⁵ are as detailed herein, or a salt thereof, comprising reacting a compound of formula 2:

The present invention provides a method which comprises reacting a compound of formula (I), where R ¹ , R ³ , R ⁴ and R ⁵ are as defined in formula (I), optionally in protected form, or a salt thereof, with a compound of formula R ¹⁵ -C(O)-X ² , where X ² is Cl, Br or I, in the presence of a base (e.g. pyridine) and a solvent (e.g. dichloromethane).

In some embodiments, R ¹⁵ is -OR ¹⁶ and the compound of formula R ¹⁵ -C(O)-X ² is a chloroformate of formula R ¹⁶ -OC(O)Cl. In some embodiments, R ¹⁵ is -NR ¹⁷ R ¹⁸ and the compound of formula 2 is reacted with a carbonylating agent (e.g., phosgene or an equivalent such as triphosgene) and an amine of formula HNR ¹⁷ R ¹⁸ in the presence of a base (e.g., pyridine) and a solvent (e.g., dichloromethane) to form a compound of formula (I). In some embodiments, R ¹⁵ is a substituted cyclopropyl group (D) and the acylating agent or equivalent of formula "R ¹⁵ -C(O)-X ² " is a substituted cyclopropanecarbonyl halide or a substituted cyclopropanecarboxylic acid activated by an activating agent.

（式中、Ｒ^１、Ｒ^３、Ｒ^４及びＲ^５は、本明細書に詳述されているとおりであり、Ｒ^１５は－ＯＲ^１６又は－ＮＲ^１７Ｒ^１８である）の化合物、又はその塩の作製方法であって、
（１）式２：

（Ｒ^１、Ｒ^３、Ｒ^４及びＲ^５は、式（Ｉ）、任意にその保護形態について定義されるとおりである）の化合物、又はその塩を、式Ｒ’－ｐｈｅｎｙｌ－Ｃ（Ｏ）Ｃｌの任意に置換されたフェニルクロロホルメート（例えば、フェニルクロロホルメート又は４－ニトロフェニルクロロホルメート）と反応させて、式２ａ：

（Ｒ’は、Ｈ又はニトロ（例えば、４－ニトロ）である）の化合物、又はその塩を形成させること、並びに
（２）式２ａの化合物、又はその塩を、（ａ）塩基（例えば、ピリジン）及び溶媒（例えば、ジクロロメタン）の存在下で式Ｒ^１６－ＯＨのアルコールと反応させて式（Ｉ）（Ｒ^１５は－ＯＲ^１６である）の化合物（若しくは式（ＩＡ）の化合物）を形成させること、又は（ｂ）式ＨＮＲ^１７Ｒ^１８のアミンと反応させて式（Ｉ）（Ｒ^１５は－ＮＲ^１７Ｒ^１８である）の化合物（若しくは式（ＩＢ）の化合物）を形成させること、
を含む、方法を提供する。 Formula (I):

wherein R ¹ , R ³ , R ⁴ and R ⁵ are as detailed herein, and R ¹⁵ is -OR ¹⁶ or -NR ¹⁷ R ¹⁸ , or a salt thereof, comprising the steps of:
(1) Formula 2:

(R ¹ , R ³ , R ⁴ and R ⁵ are as defined for formula (I), optionally in protected form thereof, or a salt thereof, is reacted with an optionally substituted phenyl chloroformate of formula R′-phenyl-C(O)Cl (e.g., phenyl chloroformate or 4-nitrophenyl chloroformate) to give a compound of formula 2a:

(R' is H or nitro (e.g., 4-nitro)), or a salt thereof; and (2) reacting a compound of formula 2a, or a salt thereof, (a) with an alcohol of formula R ¹⁶ -OH in the presence of a base (e.g., pyridine) and a solvent (e.g., dichloromethane) to form a compound of formula (I) (R ¹⁵ is -OR ¹⁶ ) (or a compound of formula (IA)), or (b) with an amine of formula HNR ¹⁷ R ¹⁸ to form a compound of formula (I) (R ¹⁵ is -NR ¹⁷ R ¹⁸ ) (or a compound of formula (IB));
The present invention provides a method comprising:

［式中、Ｒ^１、Ｒ^３及びＲ^５は式（Ｉ）又は式２、任意にその保護形態で定義されるとおりである。］の化合物、又はその塩を、式Ｒ^４－Ｂ（ＯＲ）_２［式中、ＲはＨ、任意に置換されたＣ_１－６アルキルであるか、又は２つのＯＲ基は、それらが結合するホウ素原子と共に、環（例えばボロン酸ピナコール）を形成する］と、鈴木カップリング用触媒（例えば、Ｐｄ（ｄｐｐｆ）Ｃｌ_２又は（Ｐｈ_３Ｐ）_４Ｐｄ）、塩基（例えば炭酸ナトリウム又は酢酸カリウム）、及び溶媒（例えば１，４－ジオキサンと水、又はアセトニトリルと水）の存在下で反応させ、式２の化合物を形成することを更に含む。いくつかの実施形態において、鈴木カップリング反応は高温、例えば約１００～１２０℃で実施される。

In some embodiments, the method comprises reacting a compound of Formula 1:

wherein R ¹ , R ³ and R ⁵ are as defined in formula (I) or formula 2, optionally in protected form thereof, or a salt thereof, with a compound of formula R ⁴ -B(OR) ₂ , wherein R is H, an optionally substituted C _1-6 alkyl, or the two OR groups together with the boron atom to which they are attached form a ring (e.g., a pinacol boronic acid), in the presence of a Suzuki coupling catalyst (e.g., Pd(dppf)Cl ₂ or (Ph ₃ P) ₄ Pd), a base (e.g., sodium carbonate or potassium acetate), and a solvent (e.g., 1,4-dioxane and water, or acetonitrile and water) to form a compound of formula 2. In some embodiments, the Suzuki coupling reaction is carried out at elevated temperature, for example, about 100-120° C.

Scheme 2 shows an example of a general synthetic method as in Scheme 1, where the compound of formula (I) is a compound of formula (IA), where R ³ , R ⁴ , R ⁵ and R ¹⁶ are as detailed herein for formula (IA). Introduction of R ⁴ can be achieved via Suzuki coupling with the corresponding boronic acid or boronic acid pinacol ester (R 4 -B(OR) 2 ) using a palladium-based catalyst (e.g., Pd(dppf)Cl ₂ or (Ph ₃ P) ₄ Pd) in the presence of a base (e.g., sodium carbonate or potassium acetate) in a solvent (e.g., ^1,4 -dioxane and water or acetonitrile and water). Carbamate groups can be introduced via reaction of aminoisoquinoline ₂ with the appropriate R ¹⁶ chloroformate in the presence of a base (e.g., DIEA). Alternatively, isoquinoline 2 can be converted to the corresponding phenyl carbamate 2a, followed by reaction with an ^R16 alcohol in the presence of base to form the carbamic acid bond. Removal of the protecting group can be achieved by treatment with an acid (e.g., TFA).

Scheme 3 shows an example of a general synthetic method as in Scheme 1, where the compound of formula (I) is a compound of formula (IB), where R ³ , R ⁴ , R ⁵ , R ¹⁷ and R ¹⁸ are as detailed herein for formula (IB). Introduction of R ⁴ can be achieved via Suzuki coupling with the corresponding boronic acid or boronic acid pinacol ester (R 4 ^-B (OR) ₂ ) using a palladium-based catalyst (e.g. Pd(dppf)Cl ₂ or (Ph ₃ P) ₄ Pd) in the presence of a base (e.g. sodium carbonate or potassium acetate) in a solvent (e.g. 1,4-dioxane and water or acetonitrile and water). The urea functionality can be introduced via reaction of aminoisoquinoline 2 with an appropriate amine preactivated with triphosgene in the presence of a base (e.g. DIEA). Alternatively, isoquinoline 2 can be converted to the corresponding phenyl carbamate 2a, followed by coupling with an amine in the presence of base to form the urea. Removal of the protecting group can be achieved by treatment with an acid (e.g., TFA).

Further provided is a compound of formula (I), (IA) or (IB), or a salt thereof, as described herein, produced by the described processes for making a compound of formula (I), (IA) or (IB) as above.
Pharmaceutical Compositions and Formulations

The compounds disclosed herein can be formulated into pharmaceutical compositions together with a pharma- ceutically acceptable carrier or excipient.

The compounds of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), can be formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. In accordance with this aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), in association with a pharma- ceutically acceptable excipient, diluent, or carrier.

A typical formulation is prepared by mixing a compound of formula (I) or a variant thereof, such as formulas (IA), (IB), and (IC), and a carrier, diluent, or excipient. Suitable carriers, diluents, and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water. The specific carrier, diluent, or excipient used will depend on the means and purpose to which the compound of formula (I) or a variant thereof, such as formulas (IA), (IB), and (IC), will be applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) for administration to mammals. In general, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromas, flavorings, and other known additives to provide proper presentation of the drug (i.e., a compound of formula (I) or its variants such as formulas (IA), (IB), and (IC), or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound of formula (I) or its variants such as formulas (IA), (IB), and (IC), or a stabilized form of the compound of formula (I) or its variants such as formulas (IA), (IB), and (IC) (e.g., complexed with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above excipients. The compound of formula (I) is typically formulated into a pharmaceutical dosage form to provide an easily controllable drug dose and to enable patient compliance with a given regimen.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for distribution includes a container having disposed therein the pharmaceutical formulation in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent inadvertent access to the contents of the package. In addition, the container has disposed thereon a label that describes the contents of the container. The label may also include appropriate warnings.

Drug formulations can be prepared for various routes and types of administration. For example, a compound of formula (I) having the desired purity may be mixed with a pharma- ceutically acceptable diluent, carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences (1980) ^16th edition, Osol, A. Ed.) in the form of a lyophilized formulation, a crushed powder, or an aqueous solution, as appropriate. Formulation may be carried out by mixing with a physiologically acceptable excipient or carrier, i.e., an excipient or carrier that is non-toxic to the recipient at the dosage and concentration employed, at ambient temperature, at an appropriate pH, and at the desired degree of purity. The pH of the formulation depends primarily on the particular application and the concentration of the compound, but may range from about 3 to about 8. Formulation in acetate buffer at pH 5 is a preferred embodiment.

Compounds of formula (I) may be sterile. In particular, formulations for use in in vivo administration must be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.

The compounds may typically be stored as solid compositions, lyophilized formulations, or as aqueous solutions.

Pharmaceutical compositions containing compounds of formula (I) can be formulated, dosed, and administered in a manner, i.e., amount, concentration, schedule, course, vehicle, and route of administration, consistent with good medical practice. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners. A "therapeutically effective amount" of the compound administered is the minimum amount administered with such considerations necessary to prevent, ameliorate, or treat a coagulation factor-mediated disorder. In some embodiments, the amount is below an amount that is toxic to the host or that renders the host more susceptible to bleeding.

Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin, gelatin; Examples of suitable surfactants include: proteins such as glycines or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences ^16th edition, Osol, A. Ed., 1980.

Sustained release formulations of the compounds of formula (I) can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds of formula (I), the matrices being in the form of shaped articles such as films or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and γ-L-ethyl glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid.

Formulations include those suitable for the routes of administration detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the excipients or carriers which constitute one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with liquid excipients or carriers, or finely divided solid excipients or carriers, or both, and then, optionally, shaping the product.

Formulations of a compound of formula (I) suitable for oral administration may be prepared as discrete units, such as pills, capsules, cachets, or tablets, each containing a predetermined amount of a compound of formula (I).

Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent, etc. Molded tablets may be made by molding in a suitable machine a mixture of moistened powdered active ingredient and an inert liquid diluent. The tablets may optionally be coated or grooved and are optionally formulated so as to provide a slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups, or elixirs may be prepared for oral use. Formulations of compounds of formula (I) intended for oral use may be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

For treatment of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient in an amount of 0.075 to 20% w/w. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may contain a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG 400), and mixtures thereof. The topical formulation may optionally contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

The oily phase of the emulsion may be composed of known ingredients in a known manner. Although the phase may simply comprise an emulsifier, it may also comprise a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. A hydrophilic emulsifier included with a lipophilic emulsifier may act as a stabilizer. Taken together, the emulsifier with or without a stabilizer constitutes the so-called emulsifying wax, and the wax together with the oil and fat constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. Emulsifiers and emulsion stabilizers suitable for use in the formulation include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

Aqueous suspensions of compounds of formula (I) contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

The pharmaceutical compositions of the compounds of formula (I) or its variants such as formula (IA), (IB) and (IC) can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents described above. The sterile injectable formulation can also be a solution or suspension in a sterile injectable, non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. The sterile injectable preparation can also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well.

The amount of active ingredient that can be combined with excipients or carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active ingredient, compounded with an appropriate and convenient amount of excipients or carrier materials, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution to produce infusion of a suitable volume at a rate of about 30 mL/hour.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable excipient or carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5-20% w/w, e.g., about 0.5-10% w/w, e.g., about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose and acacia or tragacanth, pastilles containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia, and mouthwashes containing the active ingredient in a suitable liquid excipient or carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for pulmonary or nasal administration have, for example, a particle size in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in micron increments such as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nostrils to reach the alveolar sacs, or by inhalation through the mouth. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds previously used to treat or prevent disorders described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, such excipients or carriers as are known in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid excipient or carrier, for example, water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose of the active ingredient, as herein above described, or an appropriate fraction thereof.

The subject matter further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary excipient or carrier for the active ingredient. The veterinary excipient or carrier is a substance useful for the purpose of administering the composition and can be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

In certain embodiments, a pharmaceutical composition comprising a compound disclosed herein further comprises a chemotherapeutic agent. In some of these embodiments, the chemotherapeutic agent is an immunotherapeutic agent.
how to use

The compounds disclosed herein find use in inhibiting the activity of the enzyme HPK1. HPK1, also called mitogen-activated protein kinase kinase kinase kinase 1 or MAP4K1, is a member of the germinal center kinases, a family of Ste20-related serine/threonine kinases. HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3, and TAK1, leading to activation of the MAPK Jnk.

In one embodiment, the subject matter disclosed herein relates to a method of inhibiting HPK1, comprising contacting HPK1 with an effective amount of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition described herein.

In one embodiment, the presently disclosed subject matter relates to a method of enhancing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition, as described herein. In certain aspects of this embodiment, the subject's T cells have at least one of improved priming, improved activation, improved migration, improved proliferation, improved survival, and improved cytolytic activity compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the activation of the T cells is characterized by an increased frequency of γ-IFN+CD8 T cells, an increased frequency of γ-IFN+CD4 T cells, or an increased amount of IL-2 or granzyme B production by the T cells compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the number of T cells is increased compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the T cells are antigen-specific CD8 T cells. In certain aspects of this embodiment, the T cells are antigen-specific CD4 T cells. In certain aspects of this embodiment, the antigen presenting cells of the subject have enhanced maturation and activation compared to before administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the antigen presenting cells are dendritic cells. In certain aspects of this embodiment, the maturation of the antigen presenting cells is characterized by an increase in the frequency of CD83+ dendritic cells. In certain aspects of this embodiment, the activation of the antigen presenting cells is characterized by an increase in the expression of CD80 and CD86 on dendritic cells. In some aspects, the compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or pharmaceutical compositions thereof, provides general priming of an immune response (e.g., a vaccine) against a tumor or virus for boosting/antiviral/tumor immunity generation.

In the methods described herein, a compound of formula (I) or variations thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition thereof, is administered to a subject having a cancer as described elsewhere herein.

In one embodiment, the subject matter disclosed herein relates to a method for treating an HPK1-dependent disorder, comprising administering to a subject in need of treatment of an HPK1-dependent disorder an effective amount of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition, as described herein. In certain aspects of this embodiment, the HPK1-dependent disorder is cancer. In certain aspects of this embodiment, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma. In certain aspects of this embodiment, the cancer has an increased amount of T cell infiltration. In certain aspects of this embodiment, the cancer cells in the subject have selectively increased expression of MHC class I antigen expression compared to before administration of the compound or composition.

In the methods described herein, the methods can further include administering a chemotherapeutic agent to the subject. In certain aspects of the present embodiment, the chemotherapeutic agent is administered to the subject simultaneously with the compound or composition. In certain aspects of the present embodiment, the chemotherapeutic agent is administered to the subject prior to administration of the compound or composition. In certain aspects of the present embodiment, the chemotherapeutic agent is administered to the subject after administration of the compound or composition.

HPK1 polynucleotides and polypeptides are known in the art (Hu et al. (1996) Genes Dev. 10:2251-2264; incorporated herein by reference in its entirety). Certain HPK1 polynucleotides and polypeptides, including human HPK1 polynucleotides, are accessible and sequences are known, e.g., nucleotides 141-2642 of GenBank Accession No. NM_007181.5 and the encoded human HPK1 polypeptide (Accession No. NP_009112.1); and nucleotides 141-2606 of GenBank Accession No. NM_001042600.2 and the encoded human HPK1 polypeptide (Accession No. NP_001036065.1).

HPK1 polypeptides contain various conserved structural motifs. They contain an amino-terminal Ste20-like kinase domain that contains an ATP-binding site. The kinase domain is followed by four proline-rich (PR) motifs that function as binding sites for SH3-containing proteins, such as CrkL, Grb2, HIP-55, Gads, Nck, and Crk. HPK1 is phosphorylated and activated in response to TCR or BCR stimulation. TCR- and BCR-induced phosphorylation of tyrosine residues located between PR1 and PR2 mediates binding to SLP-76 in T cells or BLNK in B cells via the SLP-76 or BLNK SH2 domains, which is required for kinase activation. The citron homology domain found at the C-terminus of HPK1 may function as a regulatory domain and may be involved in macromolecular interactions.

The compounds disclosed herein directly bind to HPK1 and inhibit its kinase activity. In some embodiments, the compounds disclosed herein reduce, inhibit, or otherwise decrease HPK1-mediated phosphorylation of SLP76 and/or Gads.

The compounds disclosed herein may or may not be specific HPK1 antagonists. A specific HPK1 antagonist reduces the biological activity of HPK1 by a statistically significant amount greater than the inhibitory effect of any other protein antagonist (e.g., other serine/threonine kinases). In certain embodiments, the compounds disclosed herein specifically inhibit the serine/threonine kinase activity of HPK1. In some of these embodiments, the _IC50 of the HPK1 antagonist against HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the _IC50 of the HPK1 antagonist against another serine/threonine kinase or other type of kinase (e.g., tyrosine kinase).

The compounds disclosed herein can be used in methods of inhibiting HPK1. Such methods include contacting HPK1 with an effective amount of a compound disclosed herein. By "contacting" it is intended to bring the compound sufficiently close to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., a T cell, a B cell, a dendritic cell) that the compound can bind and inhibit the activity of HPK1. The compound can be contacted with HPK1 in vitro or in vivo by administering the compound to a subject.

Any method known in the art for measuring the kinase activity of HPK1 can be used to determine whether HPK1 is inhibited, including in vitro kinase assays using antibodies specific for phosphorylated targets of HPK1, such as SLP76 and Gads, or measuring downstream biological effects of HPK1 kinase activity, such as recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of SLP76-Gads-14-3-3 from LAT-containing microclusters, or activation of T or B cells.

The compounds disclosed herein can be used to treat HPK1-dependent disorders. As used herein, an "HPK1-dependent disorder" is a condition in which HPK1 activity is necessary for the development or continuation of the condition. In some embodiments, the HPK1-dependent disorder is cancer.

The compounds disclosed herein also find use in methods of enhancing an immune response in a subject in need thereof. Such methods include administering an effective amount of a compound disclosed herein (i.e., a compound of formula (I), or variations thereof, such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt, prodrug, metabolite, or derivative thereof).

As used herein, "enhancing an immune response" means improving any immunogenic response to an antigen. Non-limiting examples of improved immunogenic responses to an antigen include improved maturation or migration of dendritic cells, improved activation of T cells (e.g., CD4 T cells, CD8 T cells), improved proliferation of T cells (e.g., CD4 T cells, CD8 T cells), improved B cell proliferation, increased survival of T cells and/or B cells, improved antigen presentation by antigen presenting cells (e.g., dendritic cells), improved antigen clearance, increased production of cytokines by T cells (e.g., interleukin-2), increased resistance to prostaglandin E2-induced immunosuppression, and improved priming and/or cytolytic activity of CD8 T cells.

In some embodiments, the subject's CD8 T cells have increased priming, activation, proliferation, and/or cytolytic activity compared to before administration of a compound of Formula (I), or variants thereof, such as Formulas (IA), (IB), and (IC), or pharma- ceutically acceptable salts, prodrugs, metabolites, or derivatives thereof. In some embodiments, priming of CD8 T cells is characterized by increased CD44 expression and/or enhanced cytolytic activity on CD8 T cells. In some embodiments, activation of CD8 T cells is characterized by an increase in the frequency of γ-IFN ⁺ CD8 T cells. In some embodiments, the CD8 T cells are antigen-specific T cells.

In some embodiments, the subject's CD4 T cells have increased priming, activation, proliferation, and/or cytolytic activity compared to before administration of a compound of Formula (I), or variants thereof, such as Formulas (IA), (IB), and (IC), or pharma-ceutically acceptable salts, prodrugs, metabolites, or derivatives thereof. In some embodiments, priming of CD4 T cells is characterized by increased CD44 expression and/or enhanced cytolytic activity on the CD4 T cells. In some embodiments, activation of CD4 T cells is characterized by an increase in the frequency of γ-IFN ⁺ CD4 T cells. In some embodiments, the CD4 T cells are antigen-specific T cells.

In some embodiments, the subject's antigen-presenting cells have enhanced maturity and activation compared to before administration of a compound of Formula (I), or variants thereof, such as Formulas (IA), (IB), and (IC), or pharma-ceutically acceptable salts, prodrugs, metabolites, or derivatives thereof. In some embodiments, the antigen-presenting cells are dendritic cells. In some embodiments, maturation of antigen-presenting cells is characterized by an increase in frequency of CD83 ⁺ dendritic cells. In some embodiments, activation of antigen-presenting cells is characterized by an increase in expression of CD80 and CD86 on dendritic cells.

In some embodiments, the serum concentration of the cytokine IL-10 and/or the chemokine IL-8, a human homolog of mouse KC, in the subject is reduced compared to before administration of a compound of formula (I), or variants thereof, such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt, prodrug, metabolite, or derivative thereof.

TCR engagement leads to activation of HPK1, which functions as a negative regulator of the TCR-induced AP-1 response pathway. It is believed that HPK1 negatively regulates T cell activation by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, thereby reducing the persistence of signaling in microclusters, leading to recruitment of phosphorylated SLP76 and 14-3-3 proteins that bind Gads, releasing the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, which leads to T cell dysfunction, including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol 195(5):839-853).

The term "impairment" in the context of immune dysfunction refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and/or anergy, in which antigen recognition can occur but the subsequent immune response is ineffective in controlling infection or tumor growth rate.

As used herein, the term "dysfunctional" also includes refractoriness or unresponsiveness to antigen recognition, specifically, impaired ability to translate antigen recognition into downstream T cell effector functions such as proliferation, cytokine production (e.g., IL-2), and/or target cell killing.

The term "anergy" refers to a state of unresponsiveness to antigenic stimulation due to defective or insufficient signals delivered via the T cell receptor (e.g., an increase in intracellular Ca ⁺² in the absence of ras activation). T cell anergy can also occur upon stimulation with antigen in the absence of costimulation, resulting in unresponsiveness to subsequent activation by antigen even in the context of costimulation. The unresponsive state can often be abrogated by the presence of interleukin-2. Anergic T cells do not undergo clonal expansion and/or acquire effector function.

The term "exhaustion" refers to T cell exhaustion as a state of T cell dysfunction due to persistent TCR signaling that occurs during many chronic infections and cancer development. It is distinct from anergy in that it is due to persistent signaling rather than defective or insufficient signaling. It is defined by poor effector function, persistent expression of inhibitory receptors, and a transcriptional state that differs from functional effector or memory T cells. Exhaustion prevents optimal control of infections and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) and cell-intrinsic negative regulatory (co-stimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

In some embodiments, administering a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt, prodrug, metabolite, or derivative thereof to a subject results in improved T cell function. In some embodiments, administering an HPK1 inhibitor described herein can improve/renew/reactivate an immune response or activate a de novo immune response.

"Enhancing T cell function" means inducing, causing, or stimulating T cells to have sustained or amplified biological function, or regenerating or reactivating exhausted or inactive T cells. Examples of improved T cell function include increased secretion of cytokines (e.g., gamma-interferon, IL-2, IL-12, and TNFα), increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) compared to pre-intervention levels, and increased production of effector granules, such as granzyme B, by CD8 T cells or CD4 T cells. In one embodiment, the level of enhancement is at least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to those skilled in the art.

Thus, the compounds of formula (I) disclosed herein, or variants thereof, such as formula (IA), (IB), and (IC), or pharma- ceutically acceptable salts, prodrugs, metabolites, or derivatives thereof, are useful for treating T cell dysfunctional disorders. A "T cell dysfunctional disorder" is a disorder or condition of T cells characterized by reduced responsiveness to antigenic stimulation. In certain embodiments, the T cell dysfunctional disorder is a disorder specifically associated with increased kinase activity of HPK1. In another embodiment, the T cell dysfunctional disorder is a disorder in which T cells are anergic or have a reduced ability to secrete cytokines, proliferate, or carry out cytolytic activity. In a particular aspect, the reduced responsiveness results in ineffective control of pathogens or tumors expressing immunogens. Examples of T cell dysfunctional disorders characterized by T cell dysfunction include unexplained acute infections, chronic infections, and tumor immunity.

The compounds disclosed herein can therefore be used in therapeutic conditions where enhanced immunogenicity is desired, such as increasing tumor immunogenicity for cancer treatment.

"Immunogenicity" refers to the ability of a particular substance to elicit an immune response. Tumors are immunogenic, and enhanced tumor immunogenicity aids in the clearance of tumor cells by the immune response. Viruses can also be immunogenic, and enhanced/activated immunogenicity can aid in the clearance of viral particles by the immune response.

"Tumor immunity" refers to the process by which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated and tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the subject has melanoma. The melanoma can be early stage or late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer can be early stage or late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer can be early stage or late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer can be early stage or late stage. In some embodiments, the subject has hematological malignancies. The hematological malignancies can be early stage or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer can be early stage or late stage. In some embodiments, the subject has breast cancer. The breast cancer can be early stage or late stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma can be early stage or late stage. In some embodiments, the cancer has increased levels of T cell infiltration.

In one aspect, a method of treating a viral infection in a subject in need of such treatment is provided, comprising administering to the subject an effective amount of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In one aspect, a method of boosting or boosting a response to a vaccine (cancer vaccine or personalized cancer vaccine (PCV)) or both CAR-T cells in a subject in need of such treatment is provided, comprising administering to the subject an effective amount of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

The compounds disclosed herein may be administered by any suitable method known in the art. In some embodiments, the compounds of formula (I), or variations thereof, such as formulas (IA), (IB), and (IC), or pharma- ceutically acceptable salts, prodrugs, metabolites, or derivatives thereof, are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally, or intranasally.

In some embodiments, the HPK1 antagonist is administered continuously. In other embodiments, the HPK1 antagonist is administered intermittently. Moreover, treatment of a subject with an effective amount of an HPK1 antagonist can include a single treatment or can include a series of treatments.

It is understood that the appropriate dose of the active compound depends on many factors within the knowledge of a physician or veterinarian in the art. The dose of the active compound will vary depending, for example, on the age, weight, general health, sex, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combinations.

Furthermore, it will be understood that the effective dosage of a compound of formula (I), or variations thereof, such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt, prodrug, metabolite, or derivative thereof, used in therapy, may increase or decrease over the course of a particular treatment. Changes in dosage will have consequences and will be evident from the results of diagnostic assays.

In some embodiments, the HPK1 antagonist is administered to the subject at a dose of about 0.001 μg/kg to about 1000 mg/kg, including, but not limited to, about 0.001 μg/kg, about 0.01 μg/kg, about 0.05 μg/kg, about 0.1 μg/kg, about 0.5 μg/kg, about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 100 μg/kg, about 250 μg/kg, about 500 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25 mg/kg, about 50 mg/kg, about 100 mg/kg, and about 200 mg/kg.

In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt, prodrug, metabolite, or derivative thereof, and further comprising administering an additional therapy. The additional therapy can be radiation therapy, surgery (e.g., tumor resection and mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplant, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing. The additional therapy can be in the form of adjuvant therapy or neoadjuvant therapy. In some embodiments, the additional therapy is administering an anti-metastatic agent. In some embodiments, the additional therapy is administering a side effect limiting agent (e.g., an agent intended to reduce the occurrence and/or severity of side effects of the treatment, such as an antiemetic agent). In some embodiments, the additional therapy is radiation therapy. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy is a combination of radiation therapy and surgery. In some embodiments, the additional therapy is gamma irradiation. In some embodiments, the additional therapy is a therapy targeting the PI3K/AKT/mTOR pathway, an HSP90 inhibitor, a tubulin inhibitor, an apoptosis inhibitor, and/or a chemopreventive agent.

The additional therapy can be one or more chemotherapeutic agents. Thus, a method of treating cancer can include administering an HPK1 antagonist disclosed herein in combination with at least one chemotherapeutic agent.

As used herein, "in conjunction with" refers to the administration of one therapeutic modality with another therapeutic modality. Thus, "in conjunction with" refers to the administration of one therapeutic modality before, during, or after the administration of another therapeutic modality to a subject.

For example, the HPK1 antagonist and the chemotherapeutic agent can be administered sequentially (at different times) or simultaneously (at the same time). The HPK1 antagonist and the chemotherapeutic agent can be administered by the same route of administration or by different routes of administration.

In certain embodiments, the HPK1 antagonist is administered with another immunotherapy. For example, the HPK1 antagonist can be combined with a chemotherapeutic or biologic agent that targets the PD-L1/PD-1 pathway. A known inhibitory checkpoint pathway involves signaling through the PD-1 receptor. The programmed cell death 1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are part of the same family as the CTLA-4 coregulatory molecules. -For more information, see http://www.conclive.com/web-exclusives/the-role-of-anti-pd-l1-immunotherapy-in-cancer/2#sthash.cGfYa1T1.dpuf. Chemotherapeutic agents or biologics that block the binding of PD-L1 to PD-1 and CD80 can prevent PD-L1-mediated inhibition/suppression of T cell activation. Programmed cell death ligand 1 (PD-L1) is broadly expressed on antigen-presenting cells (APCs) and other immune cells. It is upregulated on tumor cells from a wide range of human cancers, suggesting inhibition of antitumor T cell immunity. PD-L1 is a cell surface protein that binds to the receptors PD-1 and CD80 on activated T cells, B cells, and other myeloid cells. Binding of PD-L1 to PD-1 on activated T cells has been found to interfere with T cell proliferation and inhibit immune responses. Overexpression of PD-L1 on cancer cells may enable these cells to evade immune detection and elimination. High levels of PD-L1 expression on tumor cells are associated with increased tumor aggressiveness and poor prognosis. Chemotherapeutic or biologic agents that block the binding of PD-L1 to PD-1 include anti-PD-L1 antibodies, such as durvalumab, nivolumab, pidolizumab, MPDL3280A, MK-3475, BMS-936559, among others. In some embodiments, the HPK1 antagonist is administered with a PD-1 antagonist, such as an anti-PD-1 antibody, a PD-L1 antagonist, such as an anti-PD-L1 antibody, and/or a PD-L2 antagonist, such as a PD-L2 antibody. Examples of anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab (also known as MPDL3280A), pembrolizumab (also known as MK-3475), LY3300054 (Eli Lilly), STI-A1014 (Sorrento), KN035 (Suzhou Alphamab), and BMS-936559 (Bristol Myers Squibb). Examples of anti-PD-1 antibodies include, but are not limited to, nivolumab, pidolizumab, PDR001 (Novartis), REGN2810 (Regeneron), BGB-108 (BeiGene), BGB-A317 (BeiGene), JS-001 (Shanghai Junshi), STI-A1110 (Sorrento), INCSHR-1210 (Incyte), PF-06801591 (Pfizer), TSR-042 (also known as ANB011; Tesaro/AnaptysBio), AM0001 (ARMO Biosciences), and ENUM 244C8 (Enumeral Biomedical Holdings).

In another example, HPK1 antagonists can be combined with chemotherapeutic or biologic agents that target OX40 and its ligand, OX40L, a member of the TNF superfamily. OX40 is expressed on activated CD4(+) and CD8(+) T cells, as well as other lymphoid and non-lymphoid cells. Costimulatory signals from OX40 to conventional T cells promote division and survival, and increase clonal expansion of effector and memory populations when antigen is generated. OX40 also suppresses differentiation and activity of T regulatory cells, further amplifying this process. OX40 and OX40L also control cytokine production from T cells, antigen-presenting cells, natural killer cells, and natural killer T cells, and control cytokine receptor signaling. As one of the most prominent costimulatory molecules known to regulate T cells, stimulatory OX40 has been shown to be a target for therapeutic immunization strategies against cancer. Certain OX40 agonists include GBR 830 and those disclosed in Linch, et al., Frontiers in Oncology, v. 5, pp. 1-10 (2015), which is incorporated herein by reference in its entirety.

In another example, the HPK1 antagonist can be combined with a chemotherapeutic or biological agent that targets CD28, OX40, GITR, CD137, CD27, CD40, ICOS, HVEM, NKG2D, MICA, 2B4, IL-2, IL-12, IFNγ, IFNα, TNFα, IL-1, CDN, HMGB1, TLR, PD-L1 axis, CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7H4, CD96, CD226, prostaglandins, VEGF, endothelin B, IDO, arginase, MICA/MICB, TIM-3, IL-10, IL-4, IL-13, TIGIT, or TGFβ. In another example, the HPK1 antagonist can be combined with a PD-L1 axis, CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7H4, CD96, TIGIT, CD226, prostaglandin, VEGF, endothelin B, IDO, arginase, MICA/MICB, TIM-3, IL-10, IL-4, or IL-13 antagonist. In another example, the HPK1 antagonist can be combined with an immunotherapy that includes a CD28, OX40, GITR, CD137, CD27, CD40, ICOS, HVEM, NKG2D, MICA, 2B4, IL-2, IL-12, IFNγ, IFNα, TNFα, IL-1, CDN, HMGB1, or TLR agonist.

In another example, the HPK1 antagonist can be combined with PCV. In another example, the HPK1 antagonist can be combined with adoptive T cell therapy.

A method of inhibiting HPK1 is provided, comprising contacting HPK1 in a subject with an effective amount of a compound of formula (I), or variants thereof such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition comprising the compound of formula (I), or variants thereof such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof.

A method of enhancing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or variants thereof such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition comprising the compound of formula (I), or variants thereof such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof.

In some embodiments, the subject has cancer.

Also provided is a method for treating an HPK1-dependent disorder, comprising administering to a subject in need of treatment for an HPK1-dependent disorder an effective amount of a compound of formula (I), or variants thereof such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof; or a pharmaceutical composition comprising the compound of formula (I), or variants thereof such as formulas (IA), (IB), and (IC), or a pharma- ceutically acceptable salt thereof.

In some embodiments, the HPK1-dependent disorder is cancer.

In some embodiments, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma.

In some embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

In some embodiments, the present invention also provides a compound of formula (I) as described herein, or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, for use in a method of inhibiting HPK1 as described herein, in a method of enhancing an immune response in a subject in need thereof as described herein, and/or in a method of treating an HPK1-dependent disorder as described herein.

In some embodiments, the present invention also provides a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, for use in the methods of inhibiting HPK1 as described herein.

In some embodiments, the present invention also provides a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, for use in a method of enhancing an immune response in a subject in need thereof, as described herein.

In some embodiments, the present invention also provides a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, for use in a method for treating an HPK1-dependent disorder as described herein.

In some embodiments, the present invention also provides the use of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, for the manufacture of a medicament for inhibiting HPK1, enhancing an immune response in a subject in need thereof, and/or treating an HPK1-dependent disorder.

In some embodiments, the present invention also provides the use of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, for the manufacture of a medicament for inhibiting HPK1.

In some embodiments, the present invention also provides the use of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), as described herein, or a pharmaceutical composition as described herein, for the manufacture of a medicament for enhancing an immune response in a subject in need thereof.

In some embodiments, the present invention also provides the use of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), as described herein, or a pharmaceutical composition as described herein, for the manufacture of a medicament for treating an HPK1-dependent disorder.

In some embodiments, the present invention also provides for the use of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, in a method for inhibiting HPK1 as described herein, in a method for enhancing an immune response in a subject in need thereof as described herein, and/or in a method for treating an HPK1-dependent disorder as described herein.

In some embodiments, the present invention also provides the use of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, in a method of inhibiting HPK1 as described herein.

In some embodiments, the present invention also provides the use of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, in a method of enhancing an immune response in a subject in need of such an enhanced immune response.

In some embodiments, the present invention also provides the use of a compound of formula (I) or variants thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutical composition as described herein, in a method for treating an HPK1-dependent disorder as described herein.

In some embodiments, the treatment results in a sustained response in the subject after cessation of treatment. "Sustained response" refers to a sustained effect on reducing tumor growth after cessation of treatment. For example, the tumor size remains the same or becomes smaller compared to the size at the beginning of the dosing phase. In some embodiments, the sustained response has a duration at least as long as the treatment period, at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the treatment period.

The treatment methods disclosed herein may result in partial or complete responses. As used herein, "complete response" or "CR" means disappearance of all target lesions, "partial response" or "PR" means at least a 30% decrease in the sum of the longest diameters (SLD) of the target lesions, with reference to the baseline SLD, and "stable disease" or "SD" means that there is neither sufficient shrinkage of the target lesions since the start of treatment, with reference to the smallest SLD, to be considered PR, nor sufficient increase in the target lesions to be considered PD. As used herein, "overall response rate" (ORR) means the sum of the complete response (CR) rate and the partial response (PR) rate.

The treatment methods disclosed herein can result in increased progression-free survival and overall survival in subjects to whom an HPK1 antagonist is administered. As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not worsen. Progression-free survival may include the amount of time a patient experiences a complete or partial response, as well as the amount of time a patient experiences stable disease.

As used herein, "overall survival" refers to the proportion of subjects in a group who are likely to be alive after a particular period of time.

In some embodiments, the subject to which the HPK1 antagonist is administered is a mammal, such as a livestock animal (e.g., cows, sheep, cats, dogs, and horses), a primate (e.g., humans and non-human primates such as monkeys), a rabbit, and a rodent (e.g., mice and rats). In some embodiments, the subject to be treated is a human.

A subject in need of cancer treatment can be a human who exhibits symptoms of cancer, a human who has been diagnosed with cancer, a subject in remission from cancer, or a subject who is at high risk for developing cancer (e.g., due to a genetic predisposition, a particular diet, or environmental exposures).

In any of the described methods, in one embodiment, the subject is a human, such as a human in need of the method. The subject can be a human diagnosed with or suspected of having an HPK1-dependent disorder, such as cancer. The individual can be a human without detectable disease, but with one or more risk factors for developing cancer.

Further provided are kits for carrying out the methods detailed herein, comprising one or more compounds described herein, or pharmaceutical compositions comprising compounds described herein. The kits can employ any of the compounds disclosed herein. In one variation, the kits employ compounds described herein, or pharma- ceutically acceptable salts thereof. The kits can be used for any one or more of the uses described herein, and thus can contain instructions for use in treating an HPK1-dependent disorder, such as cancer. In some embodiments, the kits contain instructions for use in treating cancer.

The kit generally includes suitable packaging. The kit may include one or more containers containing any of the compounds described herein. Each component (if more than one component is present) may be packaged in an individual container, or several components may be combined in one container where cross-reactivity and shelf life may be acceptable. One or more components of the kit may be sterile and/or may be contained in sterile packaging.

The kits can be in unit dosage form, bulk packages (e.g., multi-dose packages), or sub-unit doses. For example, kits can be provided that contain a sufficient dose (e.g., a therapeutically effective amount) of a compound disclosed herein and/or a second pharma- ceutically active compound useful for HPK1-dependent disorders (e.g., cancer) to provide effective treatment of an individual for an extended period of time, such as one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or more. The kits can also include multiple unit doses of the compound and instructions for use, and can be packaged in sufficient quantities for storage and use in a pharmacy (e.g., a hospital pharmacy, and a compounding pharmacy).

The kit may optionally include a set of instructions, typically written instructions, although depending on the use of the components in the methods of the invention, electronic storage media (e.g., magnetic or optical disks) containing instructions are also acceptable. Instructions included with the kit generally include information regarding the components and their administration to a subject.

The following examples and detailed description are offered by way of illustration and not by way of limitation.

All samples were pre-purified by an achiral system and purity was checked prior to SFC chiral purification.
General analytical method: LCMS method

Method A: Experiments performed on an Agilent 1100 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using an Agilent SunFire-C18 3.5 μm, 4.6x50 column and a flow rate of 2.0 ml/min. The solvent system was a gradient starting from 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B) to 100% solvent B in 1.3 minutes. The final solvent system was held constant for an additional 1.2 minutes.

Method B: Experiments performed on an Agilent 1200 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using an Agilent SunFire-C18 3.5 μm, 4.6×50 column and a flow rate of 2.0 ml/min. The solvent system was a gradient starting from 95% water with 0.01% TFA (solvent A) and 5% acetonitrile with 0.01% TFA (solvent B), with a gradient to 5% solvent A and 95% solvent B in 1.4 minutes. The final solvent system was held constant for an additional 1.0 minute.
Method C: Experiments performed on an Agilent 1200 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using an Agilent Xbridge-C18, 3.5 μm, 4.6×50 mm column and a flow rate of 1.8 ml/min. The solvent system was a gradient starting from 95% water (solvent A) containing 10 mM NH ₄ HCO ₃ and 5% acetonitrile (solvent B) to 5% solvent A and 95% solvent B in 1.3 minutes. The final solvent system was held constant for an additional 1.2 minutes.
Method D: Experiments performed on an Agilent 1200 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using an Agilent Xbridge-C18, 3.5 μm, 4.6×50 mm column and a flow rate of 1.8 ml/min. The solvent system was a gradient starting from 95% water (solvent A) with 10 mM NH4HCO3, and 5% acetonitrile (solvent B), with a gradient to 5% solvent A and 95% solvent B in 1.6 minutes. The final solvent system was held constant for an additional minute.
Method E: Experiments performed on an Agilent 1200 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using an Agilent SunFire-C18 3.5 μm, 4.6×50 column and a flow rate of 2.0 ml/min. The solvent system was a gradient starting from 95% water with 0.01% TFA (solvent A) and 5% acetonitrile with 0.01% TFA (solvent B), gradient to 5% solvent A and 95% solvent B in 1.5 minutes. The final solvent system was held constant for an additional 1.0 minute.
Method F: Experiments performed on an Agilent 1200 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using an Agilent Xbridge-C18, 3.5 μm, 4.6×50 mm column and a flow rate of 1.8 ml/min. The solvent system was a gradient starting from 90% water (solvent A) containing 10 mM NH ₄ HCO ₃ , and 10% acetonitrile (solvent B), with a gradient to 5% solvent A and 95% solvent B in 1.5 minutes. The final solvent system was held constant for an additional 1.0 minute.
Method G: Experiments performed on an Agilent 1200 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using an Agilent Xbridge-C18, 3.5 μm, 4.6×50 mm column and a flow rate of 1.8 ml/min. The solvent system was a gradient starting from 95% water (solvent A) containing 10 mM NH4HCO3, and 5% acetonitrile (solvent B), with a gradient to 5% solvent A and 95% solvent B in 1.4 minutes. The final solvent system was held constant for an additional 1.0 minute.
Method H: Experiments performed on an Agilent 1200 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using a Gemini-Nx 3u, C18, 3 μm, 4.6×50 mm column and a flow rate of 1.8 ml/min. The solvent system was a gradient starting from 90% water (solvent A) with 10 mM NH4HCO3, and 10% acetonitrile (solvent B), with a gradient to 5% solvent A and 95% solvent B in 1.5 minutes. The final solvent system was held constant for an additional 1.0 minute.
Method I: Experiments performed on an Agilent 1200 HPLC with an Agilent MSD mass spectrometer using ESI as the ionization source using an XBridge-C18, 3.5 μm, 4.6×50 mm column and a flow rate of 1.8 ml/min. The solvent system was a gradient starting from 95% water (solvent A) containing 10 mM NH4HCO3, and 5% acetonitrile (solvent B), with a gradient to 5% solvent A and 95% solvent B in 1.6 minutes. The final solvent system was held constant for an additional 1.0 minute.
Method J: Experiments were performed on a Shimadzu 20AD HPLC equipped with a Shimadzu LCMS2020 mass spectrometer using ESI as the ionization source, a Shim-Pack XR-ODS C18 2.2 μm, 3.0×50 column, and a flow rate of 1.2 mL/min. The solvent system was a gradient starting from 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B) to 95% solvent B in 2.0 minutes. The final solvent system was held constant for an additional 0.7 minutes.
Method K: Experiments were performed on a Shimadzu 20AD HPLC equipped with a Shimadzu LCMS2020 mass spectrometer using ESI as the ionization source, a Shim-Pack XR-ODS C18 2.2 μm, 3.0×50 column, and a flow rate of 1.2 mL/min. The solvent system was a gradient starting from 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B) to 95% solvent B in 2.0 minutes. The final solvent system was held constant for an additional 0.7 minutes.
Method L: Experiments were performed on a Shimadzu 30AD HPLC equipped with a Shimadzu LCMS2020 mass spectrometer using ESI as the ionization source, an Ascentis Express C18 2.7 μm, 2.1×50 column, and a flow rate of 1.0 mL/min. The solvent system was a gradient starting from 95% water with 0.05% TFA (solvent A) and 5% acetonitrile with 0.05% TFA (solvent B) to 95% solvent B in 2.0 minutes. The final solvent system was held constant for an additional 0.7 minutes.
Method M: Experiments were performed on a Shimadzu 20AD XR HPLC equipped with a Shimadzu LCMS2020 mass spectrometer using ESI as the ionization source, a Poroshell HPH-C18 2.7 μm, 3.0×50 column, and a flow rate of 1.2 mL/min. The solvent system was a gradient starting from 95% water with 5 mM ammonium bicarbonate (solvent A) and 5% acetonitrile (solvent B) to 95% solvent B in 2.0 minutes. The final solvent system was held constant for an additional 0.7 minutes.
Method N: Experiments performed on an Agilent 1290 UHPLC coupled to an Agilent MSD (6140) mass spectrometer using ESI as the ionization source. A Phenomenex XB-C18, 1.7 mm, 50 x 2.1 mm column was used for LC separation with a flow rate of 0.4 mL/min. Solvent A was water with 0.1% FA and solvent B was acetonitrile with 0.1% FA. The gradient consisted of 2-98% solvent B over 7 min, holding at 98% B for 1.5 min after a 1.5 min equilibration. The LC column temperature was 40 C. UV absorbance was collected at 220 nm and 254 nm and mass spectrometry full scan was applied for all experiments.
Method O: Experiments performed on a Waters Acquity UPLC equipped with a Waters LCT Premier XE mass spectrometer using ESI ionization. LC separation used an Acquity UPLC BEH C18, 1.7 mm, 2.1 x 50 mm column and a flow rate of 0.6 mL/min. MPA (mobile phase A) was water with 0.05% TFA and MPB (mobile phase B) was acetonitrile with 0.05% TFA. The gradient consisted of 2-98% MPB over 5 min, holding at 98% B for 0.5 min after equilibration for 0.5 min. The LC column temperature was 40 ^° C. UV data was collected at 220 nm and 254 nm and mass spectrometry full scan was applied for all experiments.
Synthesis Example

工程１：ｔｅｒｔ－ブチル７－ブロモ－８－メチル－２，３－ジヒドロピリド［２，３－ｂ］［１，４］オキサジン－１－カルボキシレート

Below are general methods and procedures for preparing intermediates used to prepare the compounds listed in the tables.
Example 1
Intermediate 1: tert-Butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

Step 1: tert-Butyl 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

To a solution of 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (1 g, 4.37 mmol) in tetrahydrofuran (2 mL) was added LiHMDS (8.73 mL, 8.73 mmol, 1 mol/L) dropwise at 0 ^° C. The resulting solution was stirred under nitrogen for 0.5 h at 0 ^° C. Di-tert-butyl dicarbonate (2.85 g, 13.07 mmol) was then added and the reaction was stirred at room temperature for 2 h. The reaction was quenched with methanol (50 mL). The solvent was concentrated under vacuum. The residue was purified by silica gel flash chromatography (ethyl acetate/petroleum ether, 1/4) to give tert-butyl 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (800 mg, 2.43 mmol) as a yellow oil. LCMS (ESI) [M+H] ⁺ =329.2.
Step 2: tert-Butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

工程１：４－アミノ－３－ブロモ－２－クロロ－ベンゾニトリル

A mixture of tert-butyl 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (6.2 g, 18.83 mmol), bis(pinacolato)diboron (23.93 g, 94.22 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.76 g, 3.77 mmol), and potassium acetate (5.55 g, 56.62 mmol) in 1,4-dioxane (2 mL) was stirred under nitrogen for 2.5 hours at 90 ^° C. The solvent was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (30%) to give tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (5 g, 13.29 mmol) as a yellow oil. LCMS (ESI) [M+H] ⁺ =376.3.
Example 2
Intermediate 2: 7-bromo-8-chloro-6-fluoroisoquinolin-3-amine

Step 1: 4-Amino-3-bromo-2-chloro-benzonitrile

To a solution of 4-amino-2-chlorobenzonitrile (1.5 g, 9.83 mmol) in acetonitrile (30 mL) was added 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (1.5 g, 5.25 mmol). The solution was stirred at 25 ^° C. for 2 h. The reaction was quenched by adding a saturated solution of NaHSO ₃ (30 mL) and extracted with ethyl acetate (50 mL×2). The organic layer was concentrated and purified by flash chromatography (10% ethyl acetate in petroleum ether) to give a mixture of 4-amino-3-bromo-2-chloro-benzonitrile and 4-amino-5-bromo-2-chlorobenzonitrile (850 mg, 5/2 ratio of regioisomers, 26% yield) as a yellow solid, which was used directly in the next step. ^1H NMR (400 MHz, _CDCl3 ) δ 7.67 (s, 1H), 7.38 (d, J = 8.4 Hz, 2.6H), 6.80 (s, 1H), 6.65 (d, J = 8.4 Hz, 2.6H), 4.81 (bs, 5H), 4.71 (bs, 2H).
Step 2: 3-Bromo-2-chloro-4-iodobenzonitrile

To a suspension of CuI (51.63 g, 271.74 mmol) in acetonitrile (300 mL) was added tert-butyl nitrite (33.59 g, 326.09 mmol). The mixture was stirred at 65° C. for 10 min. 4-Amino-3-bromo-2-chloro-benzonitrile and 4-amino-5-bromo-2-chlorobenzonitrile (3/4 ratio, 25 g, 108.7 mmol) were added and the reaction mixture was stirred at 65° C. for 12 h. Upon cooling to room temperature, the mixture was quenched with saturated Na ₂ S ₂ O ₄ solution (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and purified by flash column chromatography (5% ethyl acetate in petroleum ether) to give 3-bromo-2-chloro-4-iodobenzonitrile (5 g, 31% yield) as a yellow solid. ^1H NMR (400 MHz, _CDCl3 ) 7.91 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H).
Step 3: (3-bromo-2-chloro-4-iodophenyl)methanamine

To a solution of 3-bromo-2-chloro-4-iodobenzonitrile (3 g, 8.76 mmol) in THF (30 mL) was added borane-THF (30 mL, 1 M in THF, 30 mmol). The mixture was stirred at 65 ^° C. for 3 h under N _2. Upon cooling to room temperature, the mixture was quenched by the addition of methanol (10 mL) and HCl (12 N, 10 mL). The reaction was concentrated to dryness and the residue was taken up in ethyl acetate (100 mL) and extracted with water (50 mL x 2). The organic layer was discarded and the aqueous layer was adjusted to pH 9 by the addition of a saturated aqueous solution of NaHCO ₃ . The mixture was extracted with ethyl acetate (50 mL x 3) and the combined organic layers were washed with water (10 mL x 2) and brine (10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give (3-bromo-2-chloro-4-iodophenyl)methanamine (3 g, 99% yield) as a yellow oil which was used directly in the next step. LCMS (ESI) [M+H] ⁺ = 345.9.
Step 4: N-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide

To a solution of (3-bromo-2-chloro-4-iodophenyl)methanamine (2.5 g, 7.22 mmol) in methanol (20 mL) was added methyl 2,2-diethoxyacetimidate (3.75 g, 23.26 mmol). The solution was stirred at 25 ^° C. for 12 h and then concentrated to dryness. The residue was dissolved in dichloromethane (20 mL), washed with water and brine, dried over MgSO ₄ , filtered and concentrated to give N-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide (3 g, 87% yield) as a yellow solid which was used directly in the next step. LCMS (ESI) [M+H] ⁺ =474.9.
Step 5: 7-Bromo-8-chloro-6-fluoroisoquinolin-3-amine

工程１：４アミノ－２－クロロ－３－フルオロベンゾニトリル

A mixture of sulfuric acid (10 mL) and N-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide (3 g, 6.31 mmol) was stirred at 60 ^° C. for 12 h. After the reaction mixture was cooled to 0 ^° C., NaOH solution was added to adjust the pH to 9. The resulting solution was extracted with dichloromethane (100 mL×3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to give 7-bromo-8-chloro-6-fluoroisoquinolin-3-amine (2.4 g, 99% yield) as a yellow solid. LCMS (ESI) [M+H] ⁺ =382.8. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.99 (s, 1H), 8.32 (s, 1H), 6.56 (s, 1H), 6.49 (s, 2H).
Example 3
Intermediate 3: 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine

Step 1: 4-amino-2-chloro-3-fluorobenzonitrile

To a sealed tube was added copper(I) cyanide (1.2 g, 13.37 mmol), 4-bromo-3-chloro-2-fluoroaniline (1 g, 4.46 mmol) and 1-methyl-2-pyrrolidinone (8 mL). The mixture was heated in a microwave reactor at 170 ^° C. for 1 h. The reaction mixture was quenched by addition of a saturated solution of NH ₄ Cl (20 mL) and filtered. The filtrate was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (3×10 mL), dried over Na ₂ SO ₄ , filtered through a pad of silica gel and concentrated to dryness to give 4-amino-2-chloro-3-fluorobenzonitrile (700 mg, 92% yield) as a yellow solid. LCMS (ESI) [M+H] ⁺ =171.1.
Step 2: 2-Chloro-3-fluoro-4-iodobenzonitrile

To a suspension of CuI (3341 mg, 17.59 mmol) in acetonitrile (50 mL) was added tert-butyl nitrite (1811 mg, 17.59 mmol) at 65 ^° C. under N _2. The mixture was stirred at 65° C. for 10 min, after which 4-amino-2-chloro-3-fluorobenzonitrile (2 g, 11.73 mmol) was added. The mixture was stirred at 65° C. for 12 h. Upon cooling to room temperature, the mixture was quenched with saturated aqueous Na ₂ S ₂ O ₄ (30 mL) and aqueous NH ₄ Cl (30 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give the crude product, which was purified by flash chromatography (petroleum ether/ethyl acetate=5/1) to give 2-chloro-3-fluoro-4-iodobenzonitrile (1 g, 30% yield) as a yellow solid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (dd, J=5.6, 8.2 Hz, 1H), 7.22 (dd, J=1.4, 8.2 Hz, 1H).
Step 3: (2-chloro-3-fluoro-4-iodophenyl)methanamine

2-Chloro-3-fluoro-4-iodobenzonitrile (1 g, 3.55 mmol) was added to a solution of borane-THF (35.53 mL, 1 M in THF, 35.53 mmol) in THF (30 mL) at 0 ^° C. The mixture was then warmed to room temperature and stirred overnight. The reaction solution was quenched by dropwise addition of HCl solution (6 M, 2 mL), then neutralized with an aqueous solution of NaHCO ₃ to pH=8 and extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water (2×10 mL) and brine (1×10 mL), dried (Na ₂ SO ₄ ), filtered and concentrated to give (2-chloro-3-fluoro-4-iodophenyl)methanamine (400 mg, crude), which was used directly in the next step without further purification. LCMS (ESI) [M+H] ⁺ =285.9.
Step 4: N-(2-chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide

To a solution of methyl 2,2-diethoxyacetimidate (0.3 g, 1.88 mmol) in methanol (5 mL) was added (2-chloro-3-fluoro-4-iodophenyl)methanamine (250 mg, 0.88 mmol). The reaction mixture was stirred at 25 ^° C. for 12 h and then concentrated to dryness. The residue was taken up in dichloromethane (20 mL), washed with water (2×10 mL) then brine, dried (MgSO ₄ ), filtered and concentrated to give N-(2-chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide (360 mg, crude) as a yellow solid which was used directly in the next step without further purification. LCMS (ESI) [M+H] ⁺ =415.0.
Step 5: 8-Chloro-7-fluoro-6-iodoisoquinolin-3-amine

工程１：（４－ブロモ－３－フルオロフェニル）メタンアミン

A solution of N-(2-chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide (0.36 g, 0.87 mmol) and concentrated H ₂ SO ₄ (10 mL, 26.05 mmol) was stirred at 60 ^° C. for 12 h. The mixture was cooled to 0 ^° C. and adjusted to pH=9 with NaOH (10 wt%) before being extracted with dichloromethane (5×100 mL). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine (0.25 g, crude) as a yellow solid which was used directly without further purification. LCMS (ESI) [M+H] ⁺ =322.9. ^1H NMR (400 MHz, _CD3OD ) δ 9.00 (s, 1H), 8.08 (d, J=5.6 Hz, 1H), 6.70 (s, 1H).
Example 4
Intermediate 4: 6-bromo-7-fluoroisoquinolin-3-amine

Step 1: (4-bromo-3-fluorophenyl)methanamine

A solution of 4-bromo-3-fluoro-benzonitrile (5.0 g, 25 mmol) in BH3.THF ( ₈₀ mL, 1 mol/L, 80 mmol) was stirred at 60° C. for 3 h. The reaction was quenched with MeOH (20 mL) and HCl (20 mL, 12 M). The resulting solution was extracted with EtOAc (3 _× 200 mL), dried over anhydrous MgSO4, and concentrated under vacuum to give (4-bromo-3-fluorophenyl)methanamine (4.5 g, crude), which was used directly in the next step without purification. LCMS (ESI) [M+H] ⁺ =204.
Step 2: Methyl 2,2-diethoxyacetimidate

A solution of 2,2-diethoxyacetonitrile (4.0 g, 30.97 mmol) and sodium methoxide (1.2 mL, 5.4 mol/L, 6.19 mmol) in methyl alcohol (40 mL) was stirred at 25° C. for 3 h and then concentrated to dryness. The residue was taken up in dichloromethane (200 mL), washed with water (3×80 mL) and brine, dried over anhydrous MgSO ₄ , filtered and concentrated under vacuum to give methyl 2,2-diethoxyacetimidate (5 g, crude), which was used directly in the next step without further purification. LCMS (ESI) [M+H] ⁺ =162.
Step 3: N-(4-bromo-3-fluorobenzyl)-2,2-diethoxyacetimidamide

A solution of (4-bromo-3-fluoro-phenyl)methanamine (4.5 g, crude), methyl 2,2-diethoxyethanimidate (5 g, crude) in methyl alcohol (40 mL) was stirred at 25° C. for 3 h. The reaction was concentrated to dryness and the residue was taken up in dichloromethane. The organic layer was washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give N-(4-bromo-3-fluorobenzyl)-2,2-diethoxyacetimidamide (5.0 g, crude), which was used in the next step without further purification. LCMS (ESI) [M+H] ⁺ =333.
Step 4: 6-Bromo-7-fluoroisoquinolin-3-amine

A solution of N-[(4-bromo-3-fluoro-phenyl)methyl]-2,2-diethoxy-acetamidine (5.0 g, crude) in H ₂ SO ₄ (30 mL) was stirred at 60 ^° C. for 12 h. The reaction mixture was cooled to 0° C. and NaOH was added to adjust pH=9. The mixture was extracted with DCM (3×150 mL). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. The residue was purified on a silica gel column eluted with EA/PE (3/7) to give a mixture of 6-bromo-7-fluoroisoquinolin-3-amine and 6-bromo-5-fluoroisoquinolin-3-amine (800 mg, 6:6a=5:1, 3.32 mmol) as a yellow solid. LCMS (ESI) [M+H] ⁺ =241.
Example 5
Intermediate 5: 2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid Step 1: Diphenyl(propyl)sulfonium tetrafluoroborate

To a solution of silver tetrafluoroborate (2 g, 10.31 mmol) in dichloromethane (20 mL) at 0° C. was added 1-iodopropane (1.75 g, 10.31 mmol) and diphenyl sulfide (5.76 g, 30.93 mmol). The reaction was stirred at 35 ^° C. for 15 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with dichloromethane-ether to give diphenyl(propyl)sulfonium tetrafluoroborate (2 g, 6.32 mmol) as a white solid. LCMS (ESI) [M+H] ⁺ = 229.
Step 2: trans-tert-butyl 2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate

To a solution of diphenyl(propyl)sulfonium tetrafluoroborate (1.50 g, 4.75 mmol) in 1,2-dimethoxyethane (30 mL) and dichloromethane (3 mL) at −78 ^° C. was added lithium diisopropylamide (5.54 ml, 11.09 mmol). The resulting mixture was stirred at −78 ^° C. for 1 hour. Then tert-butyl (Z)-3-(1-methylpyrazol-4-yl)prop-2-enoate (330 mg, 1.58 mmol) was added and stirred at −78 ^° C. to 25° C. for 15 hours. The reaction was quenched with water. The resulting mixture was extracted with dichloromethane and dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated in vacuo to give trans-tert-butyl 2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate as a brown oil as a mixture of four stereoisomers in which the pyrazole is trans to the ester (350 mg, 1.40 mmol). LCMS (ESI) [M+H] ⁺ =251.
Step 3: trans-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid

A solution of trans-tert-butyl 2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate (350 mg, 1.4 mmol) and 2,2,2-trifluoroacetic acid (8 mL) in dichloromethane (3 mL) was stirred at 25 ^° C. for 1 h. The mixture was concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (acetonitrile 0-40/0.1% HCl in water) to give trans-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid (260 mg, 1.34 mmol) as a brown oil. LCMS (ESI) [M+H] ⁺ =195.
Intermediate 6: 2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid Step 1: Ethyldiphenylsulfanium tetrafluoroborate

To a solution of _AgBF4 (37.48 g, 192.53 mmol) in dichloromethane (450 mL) was added iodoethane (30 g, 192.35 mmol) under nitrogen. The solution was stirred at room temperature for 30 min. Phenylsulfanyl)benzene (106.92 g, 573.99 mmol) was added and then stirred at 35 ^° C for 16 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was washed with dichloromethane/ether (1/1) to give ethyl diphenylsulfanium tetrafluoroborate (25 g, 116.28 mmol) as an off-white solid. LCMS (ESI) [M+H] ⁺ = 215.
Step 2: trans-tert-butyl 2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate

To a solution of ethyl(diphenyl)sulfonium (1.55 g, 7.2 mmol) in dichloromethane (2 mL) and 1,2-dimethoxyethane (20 mL) at −78 ^° C. was added lithium diisopropylamide (4.2 mL, 8.4 mmol). The resulting solution was stirred at −78 ^° C. for 1 h. tert-Butyl (E)-3-(1-methylpyrazol-4-yl)prop-2-enoate (500 mg, 2.4 mmol) was added at −78 ^° C. The mixture was stirred at 25 ^° C. for 6 h. The reaction was quenched with water and then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give trans-tert-butyl 2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate (550 mg, crude) as a yellow oil. LCMS (ESI) [M+H] ⁺ =237.
Step 3: (±)-trans-tert-butyl 2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate

工程１：シクロプロピルメチル２－クロロアセテート

A solution of trans-tert-butyl 2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylate (500 mg, crude) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (4 mL) was stirred at 25 ^° C. for 2 h. The solvent was concentrated under vacuum. The reaction mixture was adjusted to pH 7 with ammonia in methanol (7 mol/L). The residue was purified by reverse phase chromatography (acetonitrile 0-40/0.1% HCl in water) to give a mixture of four stereoisomers of 2-methyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid (180 mg, 0.99 mmol) in which the pyrazole is trans to the carboxylic acid as a yellow oil. LCMS (ESI) [M+H] ⁺ =181.
Example 101
Cyclopropylmethyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 101)

Step 1: Cyclopropylmethyl 2-chloroacetate

A solution of triphosgene (1.5 g, 5.1 mmol) in dichloromethane (5.0 mL) was added dropwise to a solution of cyclopropylmethanol (1.0 g, 13.9 mmol) and DIEA (2.2 g, 16.6 mmol) in dichloromethane (5.0 mL) at 0° C. The reaction mixture was then stirred at 20° C. for 1 h. The resulting solution was concentrated in vacuo. The crude product was used directly in the next step without any purification.
Step 2: tert-Butyl 7-[3-(cyclopropylmethoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (100 mg, 0.2 mmol), cyclopropylmethyl 2-chloroacetate (108.6 mg, 0.7 mmol) and DIEA (188.6 mg, 1.5 mmol) in dichloromethane (4.0 mL) was stirred at 25° C. for 2 h. The resulting solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (4/1) to give tert-butyl 7-[3-(cyclopropylmethoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (19.0 mg, 0.04 mmol, 15.3% yield) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 509.2.
Step 3: Cyclopropylmethyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate

工程１：ｔｅｒｔ－ブチルＮ－ｔｅｒｔ－ブトキシカルボニル－Ｎ－［５－［３－（シクロプロピルメトキシカルボニルアミノ）－７－フルオロ－６－イソキノリル］－４－メチル－３－ピリジル］カルバメート

A solution of tert-butyl 7-[3-(cyclopropylmethoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (100 mg, 0.2 mmol) and trifluoroacetic acid (1.0 mL) in dichloromethane (4.0 mL) was stirred at 25° C. for 1 h. The reaction solution was concentrated under vacuum. The pH value of the residue was adjusted to pH 8 with ammonia in methanol (7 mol/L). The precipitate was collected by filtration to give N-[7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (36.9 mg, 0.091 mmol, 45.9% yield) as a yellow solid. LCMS (ESI) [M+H] ⁺ =409.2, Rt=2.499 min, Method=K. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.12 (s, 1H), 8.23 (s, 1H), 7.92-7.85 (m, 2H), 7.38 (s, 1H), 6.01-5.35 (m, 1H), 4.31 (s, 2H), 4.01 (d, J=9.0 Hz, 2H), 3.36 (s, 2H), 1.89 (s, 3H), 1.21-1.14 (m, 1H), 0.56 (d, J=18 Hz, 2H), 0.33 (d, J=6.0 Hz, 2H).
Example 102
Cyclopropylmethyl(6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)carbamate (Compound 102)

Step 1: tert-Butyl N-tert-butoxycarbonyl-N-[5-[3-(cyclopropylmethoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate

A solution of tert-butyl N-[5-(3-amino-7-fluoro-6-isoquinolyl)-4-methyl-3-pyridyl]-N-tert-butoxycarbonyl-carbamate (150 mg, 0.3 mmol) and pyridine (126.5 mg, 1.6 mmol) in dichloromethane (10 mL) was stirred for 10 minutes at 0° C. Cyclopropylmethylcarbonochloridate (0.91 mL, 0.6 mmol) was then added slowly dropwise, followed by stirring for 2 hours at 0° C. The resulting solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (1/1) to give tert-butyl N-tert-butoxycarbonyl-N-[5-[3-(cyclopropylmethoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate (120 mg, 0.2 mmol, 66.1% yield) as a yellow solid. LCMS (ESI) [M+H] ⁺ =567.2.
Step 2: Cyclopropylmethyl(6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)carbamate

工程１：ｔｅｒｔ－ブチル ７－［７－フルオロ－３－［（４－ニトロフェノキシ）カルボニルアミノ］－６－イソキノリル］－８－メチル－２，３－ジヒドロピリド［２，３－ｂ］［１，４］オキサジン－１－カルボキシレート

A solution of tert-butyl N-tert-butoxycarbonyl-N-[5-[3-(cyclopropylmethoxycarbonylamino)-7-fluoro-6-isoquinolyl]-4-methyl-3-pyridyl]carbamate (120 mg, 0.2 mmol) and trifluoroacetic acid (1.0 mL) in dichloromethane (4 mL) was stirred at 20° C. for 1 h. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile 0-40/0.1% NH ₄ HCO ₃ in water) to give cyclopropylmethyl(6-(5-amino-4-methylpyridin-3-yl)-7-fluoroisoquinolin-3-yl)carbamate (61.1 mg, 0.167 mmol, 78.7% yield) as a white solid. LCMS (ESI) [M+H] ⁺ = 367.2, Rt = 2.137 min, Method = K; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.13 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.95 (d, J = 10.0 Hz, 1H), 7.89 (d, J = 7.1 Hz, 1H), 7.72 (s, 1H), 5.40 (s, 2H), 3.99 (d, J = 7.2 Hz, 2H), 1.92 (d, J = 1.7 Hz, 3H), 1.25-1.12 (m, 1H), 0.60-0.51 (m, 2H), 0.38-0.29 (m, 2H).
Example 103
(R)-1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea and (S)-1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea (Compounds 201a and 201b)

Step 1: tert-Butyl 7-[7-fluoro-3-[(4-nitrophenoxy)carbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.4 mmol), pyridine (288.7 mg, 3.7 mmol) and 4-nitrophenyl chloroformate (81 mg, 0.4 mmol) in dichloromethane (10 mL) was stirred for 4 h at 25 ^° C. The mixture was then concentrated under vacuum and purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (5/1) to give tert-butyl 7-[7-fluoro-3-[(4-nitrophenoxy)carbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (180 mg, 0.3 mmol, 85.6% yield) as a yellow solid. LCMS (ESI, m/z) [M+H] ⁺ = 576.2.
Step 2: tert-Butyl 7-[7-fluoro-3-[1-(1-methylpyrazol-4-yl)ethylcarbamoylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

To a solution of tert-butyl 7-[7-fluoro-3-[(4-nitrophenoxy)carbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (200 mg, 0.40 mmol) and pyridine (0.08 mL, 1.0 mmol) in dichloromethane (30 mL) was added 1-(1-methyl-1H-pyrazol-4-yl)ethanamine (52.2 mg, 0.4 mmol) at 0° C. The resulting solution was stirred at 25° C. for 4 hours. The reaction was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10/1) to give tert-butyl 7-[7-fluoro-3-[1-(1-methylpyrazol-4-yl)ethylcarbamoylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (60 mg, 0.1 mmol, 30.7% yield) as a brown solid. LCMS (ESI) [M+H] ⁺ =562.2.
Step 3: (R)-1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea and (S)-1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea

A solution of tert-butyl 7-[7-fluoro-3-[1-(1-methylpyrazol-4-yl)ethylcarbamoylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (70 mg, 0.1 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (20 mL) was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum and purified by preparative HPLC (XBridge Prep OBD C18 Column 30×150 mm 5 μm; Water (10 MMOL/L NH ₄ HCO ₃ ): CH ₃ CN=20% B to 43% B, 7 min; 60 mL/min) to give the racemic product. The racemic product was separated by chiral-HPLC to give the two enantiomers. Absolute stereochemistry was assigned arbitrarily.

Enantiomer 1 (compound 201a) (13.2 mg, 22.9% yield): Retention time: 2.148 min (Repaired Chiral-IA, 0.46*10 cm; 5 μm; MtBE (20 mM NH ₃ ·MeOH):EtOH=70:30, 5 min; 1.0 mL/min); LCMS (ESI) [M+H] ⁺ = 462.2, Rt = 2.253 min, Method = M; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 9.02 (s, 1H), 7.82 (s, 1H), 7.74-7.72 (m, 2H), 7.61 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 5.05-5.03 (m, 1H), 4.47-4.38 (m, 2H), 3.89 (s, 3H), 3.51 (t, J = 4.4 Hz, 2H), 2.02 (d, J = 1.8 Hz, 3H), 1.57 (d, J = 6.8 Hz, 3H).

工程１：ｔｅｒｔ－ブチル７－［７－フルオロ－３－［（４－ニトロフェノキシ）カルボニルアミノ］－６－イソキノリル］－８－メチル－２，３－ジヒドロピリド［２，３－ｂ］［１，４］オキサジン－１－カルボキシレート

Enantiomer 2 (compound 201b) (17.9 mgl, 31.1% yield): Retention time: 3.003 min (Repaired Chiral-IA, 0.46*10 cm; 5 μm; MtBE (20 mM NH ₃ ·MeOH):EtOH=70:30, 5 min, 1.0 mL/min); LCMS (ESI) [M+H] ⁺ = 462.2, Rt = 2.241 min, Method = M; ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 9.02 (s, 1H), 7.82 (s, 1H), 7.74-7.72 (m, 2H), 7.61 (s, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 5.05-5.03 (m, 1H), 4.47-4.38 (m, 2H), 3.89 (s, 3H), 3.51 (t, J = 4.4 Hz, 2H), 2.02 (d, J = 1.8 Hz, 3H), 1.57 (d, J = 6.8 Hz, 3H).
Example 104
1-(cyclopropylmethyl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea (Compound 202)

Step 1: tert-Butyl 7-[7-fluoro-3-[(4-nitrophenoxy)carbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (200 mg, 0.5 mmol), pyridine (115.6 mg, 1.5 mmol) and 4-nitrophenyl chloroformate (147.3 mg, 0.7 mmol) in dichloromethane (4 mL) was stirred at room temperature for 2 h. The resulting solution was concentrated in vacuo. The crude product was used directly in the next step without any purification.
Step 2: tert-Butyl 7-[3-(cyclopropylmethylcarbamoylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl 7-[7-fluoro-3-[(4-nitrophenoxy)carbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (crude), cyclopropanemethylamine (70 mg, 1.0 mmol) and pyridine (77.8 mg, 1.0 mmol) in dichloromethane (3 mL) was stirred for 2 h at 25 ^° C. The solvent was concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile 0-40/0.1% NH ₄ HCO ₃ in water) to give tert-butyl 7-[3-(cyclopropylmethylcarbamoylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.3 mmol, 61% yield over two steps) as a yellow solid.
Step 3: 1-(cyclopropylmethyl)-3-[7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]urea

工程１：ｔｅｒｔ－ブチル７－［７－フルオロ－３－［（４－ニトロフェノキシ）カルボニルアミノ］－６－イソキノリル］－８－メチル－２，３ ジヒドロピリド［２，３－ｂ］［１，４］オキサジン－１－カルボキシレート

A solution of tert-butyl 7-[3-(cyclopropylmethylcarbamoylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.3 mmol) and trifluoroacetic acid (2.0 mL, 0.3 mmol) in dichloromethane (4 mL) was stirred at 25° C. for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 0-40/0.1% NH ₄ HCO ₃ in water) to give 1-(cyclopropylmethyl)-3-[7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]urea (77.7 mg, 0.2 mmol, 64.5%) as a white solid. LCMS (ESI) [M+H] ⁺ =408.1, Rt=2.477 min, Method=L. ¹ H NMR (300 MHz, methanol-d ₄ ) δ 9.01 (s, 1H), 7.80-7.65 (m, 3H), 7.37 (s, 1H), 4.44-4.35 (m, 2H), 3.48 (t, J=4.4 Hz, 2H), 3.18 (d, J=6.9 Hz, 2H), 1.99 (d, J=1.8 Hz, 3H), 1.14-0.99 (m, 1H), 0.59-0.48 (m, 2H), 0.28 (dt, J=6.0, 4.5 Hz, 2H).
Example 105
(R)-1-(1-cyanopropan-2-yl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea and (S)-1-(1-cyanopropan-2-yl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea (Compound 203a and Compound 203b)

Step 1: tert-Butyl 7-[7-fluoro-3-[(4-nitrophenoxy)carbonylamino]-6-isoquinolyl]-8-methyl-2,3 dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (200 mg, 0.5 mmol), 4-nitrophenyl chloroformate (108 mg, 0.5 mmol) and pyridine (385 mg, 4.9 mmol) in dichloromethane (4 mL) was stirred for 1 h at 25° C. The crude product was used directly in the next step without any purification.
Step 2: tert-Butyl 7-[3-[(2-cyano-1-methyl-ethyl)carbamoylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl 7-[7-fluoro-3-[(4-nitrophenoxy)carbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (crude), 3-aminobutanenitrile (32.2 mg, 0.4 mmol) and pyridine (274.5 mg, 3.5 mmol) in dichloromethane (4 mL) was stirred for 1.5 h at 25° C. The reaction was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10/1) to give tert-butyl 7-[3-[(2-cyano-1-methyl-ethyl)carbamoylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (130 mg, 0.2 mmol, 51% yield) as a yellow solid. LCMS (ESI) [M+H] ⁺ =521.2.
Step 3: (R)-1-(1-cyanopropan-2-yl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea and (S)-1-(1-cyanopropan-2-yl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea

A solution of trifluoroacetic acid (1.0 mL) and tert-butyl 7-[3-[(2-cyano-1-methyl-ethyl)carbamoylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (120 mg, 0.2 mmol) in dichloromethane (2 mL) was stirred at 25° C. for 1 h. The reaction solution was concentrated under vacuum. The pH value of the residue was adjusted to pH 10 with ammonia in methanol (7 mol/L). The resulting residue was purified by reverse phase chromatography (acetonitrile 0-40/0.1% NH ₄ HCO ₃ in water) to give the racemic product. The racemic product was separated by chiral-HPLC to give the two enantiomers. The absolute stereochemistry was arbitrarily assigned.

Enantiomer 1 (compound 203a) (42.5 mg, 0.1 mmol, 35% yield): Retention time: 3.516 min (CHIRALPAK IC-3; 0.46*10 cm; 3 μm; MtBE (0.1% DEA):EtOH=70:30, 18 min; Flow rate: 10 mL/min). LCMS (ESI) [M+H] ⁺ = 421.1, Rt = 1.277 min, Method = J. ^1H NMR (300 MHz, DMSO- _d6 ) δ 9.11 (s, 1H), 9.07 (s, 1H), 8.14 (s, 1H), 7.89 (d, J = 10.1 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.21 (d, J = 7.3 Hz, 1H), 5.72 (s, 1H), 4.30 (s, 2H), 4.15-3.88 (m, 1H), 3.38 (s, 2H), 2.82 (dd, J = 9.6, 5.4 Hz, 2H), 1.92 (d, J = 1.8 Hz, 3H), 1.26 (d, J = 6.7 Hz, 3H).

工程１：ｔｅｒｔ－ブチル７－［７－フルオロ－３－（テトラヒドロピラン－４－イルカルバモイルアミノ）－６－イソキノリル］－８－メチル－２，３－ジヒドロピリド［２，３－ｂ］［１，４］オキサジン－１－カルボキシレート

Enantiomer 2 (compound 203b) (45.3 mg, 0.1 mmol, 36% yield): Retention time: 4.497 min (CHIRALPAK IC-3; 0.46*10 cm; 3 μm; MtBE (0.1% DEA):EtOH=70:30, 18 min; Flow rate: 10 mL/min). LCMS (ESI) [M+H] ⁺ =421.1, Rt=1.277 min, Method=J. ^1H NMR (300 MHz, DMSO- _d6 ) δ 9.11 (s, 1H), 9.07 (s, 1H), 8.14 (s, 1H), 7.89 (d, J = 10.1 Hz, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.21 (d, J = 7.3 Hz, 1H), 5.72 (s, 1H), 4.30 (s, 2H), 4.15-3.88 (m, 1H), 3.38 (s, 2H), 2.82 (dd, J = 9.6, 5.4 Hz, 2H), 1.92 (d, J = 1.8 Hz, 3H), 1.26 (d, J = 6.7 Hz, 3H).
Example 106
1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)urea (Compound 204)

Step 1: tert-Butyl 7-[7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

A solution of tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.4 mmol), triphosgene (170 mg, 0.6 mmol) and pyridine (0.1 mL, 1.3 mmol) in tetrahydrofuran (30 mL) was stirred at 0 ^° C for 10 minutes. Tetrahydro-2H-pyran-4-amine (370 mg, 3.6 mmol) was added and the reaction was stirred at 0 ^° C for 2 hours. The resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (1/5) to give tert-butyl 7-[7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (100 mg, 0.19 mmol, 50.9% yield) as a brown solid. LCMS (ESI) [M+H] ⁺ =538.2.
Step 2: 1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)urea

工程１：ｔｒａｎｓ－ｔｅｒｔ－ブチル７－［３－［［（１Ｓ，２Ｓ）－２－エチル－３－（１－メチルピラゾール－４－イル）シクロプロパンカルボニル］アミノ］－７－フルオロ－６－イソキノリル］－８－メチル－２，３－ジヒドロピリド［２，３－ｂ］［１，４］オキサジン－１－カルボキシレート

A solution of tert-butyl 7-[7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (100 mg, 0.19 mmol) in dichloromethane (15 mL) and TFA (3 mL) was stirred at 25° C. for 1 h. The resulting solution was concentrated in vacuo. The residue was dissolved in methanol and adjusted to pH 8 with ammonia in methanol (7 mol/L). The resulting solution was concentrated under vacuum and purified by preparative HPLC (YMC-Actus Triart C18 30*250, 5 μm; Water (10 mmol/L NH ₄ HCO ₃ ):CH ₃ CN=33% B to 58% B, 7 min; 60 mL/min) to give 1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)urea (61.6 mg, 0.14 mmol, 75.7% yield) as a white solid. LCMS (ESI) [M+H] ⁺ =438.2, Rt=1.197 min, Method=M. ^1H NMR (300 MHz, DMSO- _d6 ) δ 9.06 (s, 1H), 8.98 (s, 1H), 8.12 (s, 1H), 7.87 (d, J = 10.1 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.05 (d, J = 7.4 Hz, 1H), 5.73 (s, 1H), 4.30 (s, 2H), 3.84 (d, J = 11.7 Hz, 3H), 3.41-3.45 (m, 4H), 1.92 (d, J = 1.8 Hz, 3H), 1.87 (s, 1H), 1.83 (s, 1H), 1.51-1.32 (m, 2H).
Example 107
(1R,2S,3R)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide;
(1S,2R,3S)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide;
(1S,2S,3S)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide; and (1R,2R,3R)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (Compound 301a; Compound 301b; Compound 301c; and Compound 301d).

Step 1: trans-tert-butyl 7-[3-[[(1S,2S)-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

Phosphoryl chloride (590 mg, 3.9 mmol) was added to a solution of trans-[(1S,3S)-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarboxylic acid (250 mg, 1.3 mmol) and tert-butyl 7-(3-amino-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (480 mg, 1.2 mmol) in dichloromethane (10 mL) and pyridine (2 mL) at 0° C. The reaction was stirred at 0° C. for 30 minutes and then quenched by the addition of water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (1/2) to give trans-tert-butyl 7-[3-[[(1S,2S)-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (500 mg, 0.9 mmol, 66.2% yield) as a yellow solid. LCMS (ESI) [M+H] ⁺ =587.7.
Step 2: (1R,2S,3R)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide, (1S,2R,3S)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide (1S,2S,3S)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide and (1R,2R,3R)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide.

A solution of trans-tert-butyl 7-[3-[[(1S,2S)-2-ethyl-3-(1-methylpyrazol-4-yl)cyclopropanecarbonyl]amino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (500 mg, 0.85 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (5 mL) was stirred at 25° C. for 3 h. The reaction solution was concentrated under vacuum. The pH value of the residue was adjusted to pH 7 with ammonia in methanol (7 mol/L). The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase chromatography (acetonitrile 0-40/0.1% NH ₄ HCO ₃ in water) to give the racemic mixture. The mixture was separated by chiral-HPLC to give the four isomers. The pyrazole is trans to the amide; the ethyl relative stereochemistry is arbitrarily assigned. All absolute stereochemistry was arbitrarily assigned.

Isomer 1 (compound 301a) (40 mg, 0.08 mmol, 9.6% yield): Retention time: 2.736 (Repaired Chiral-IA, 0.46*10 cm; 5 μm; MtBE (0.1% DEA):MeOH=80:20, 10 min; 1 mL/min). LCMS (ESI) [M+H] ⁺ =487.2, Rt=2.372 min, Method=J; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 9.14 (s, 1H), 8.53 (s, 1H), 7.93 (d, J=10.0 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 7.25 (s, 1H), 5.73 (d, J=2.8 Hz, 1H), 4.30-4.20 (m, 2H), 3.76 (s, 3H), 3.40 (s, 2H) 2.23-2.15 (m, 2H), 1.92 (s, 3H), 1.80-1.75 (m, 1H), 1.62-1.55 (m, 1H), 1.52-1.40 (m, 1H), 0.92-0.90 (m, 3H).

Isomer 2 (compound 301b) (39.7 mg, 0.08 mmol, 9.5% yield): Retention time: 3.219 (Repaired Chiral-IA, 0.46*10 cm; 5 μm; MtBE (0.1% DEA):MeOH=80:20, 10 min; 1 mL/min). LCMS (ESI) [M+H] ⁺ = 487.2, Rt = 1.379 min, Method = J; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 9.14 (s, 1H), 8.53 (s, 1H), 7.93 (d, J = 10.0 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 7.25 (d, J = 0.8 Hz, 1H), 5.73 (d, J = 2.7 Hz, 1H), 4.30-4.20 (m, 2H), 3.76 (s, 3H), 2.23-2.15 (m, 2H), 2.30-2.10 (m, 2H), 1.92 (s, 3H), 1.75-1.65 (m, 1H), 1.65-1.57 (m, 2H), 0.92-0.80 (m, 3H).

Isomer 3 (compound 301c) (38.5 mg, 0.08 mmol, 9.3% yield): Retention time: 3.921 (Repaired Chiral-IA, 0.46*10 cm; 5 μm; MtBE (0.1% DEA):MeOH=80:20, 10 min; Flow rate: 1 mL/min). LCMS (ESI) [M+H] ⁺ = 487.2, Rt = 1.377 min, Method = J; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 9.16 (s, 1H), 8.51 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 5.72 (s, 1H), 4.30-4.20 (m, 2H), 3.80 (s, 3H), 3.40-3.30 (m, 2H), 2.40-2.35 (m, 1H), 2.19-2.10 (m, 1H), 1.92 (s, 3H), 1.58-1.46 (m, 1H), 1.31-1.15 (m, 2H), 0.89-0.80 (m, 3H).

工程１：３－ブロモ－４－メチル－１－オキシド－ピリジン－１－イウム

Isomer 4 (compound 301d) (38.4 mg, 0.078 mmol, 9.2% yield): Retention time: 4.813 (Repaired Chiral-IA, 0.46*10 cm; 5 μm; MtBE (0.1% DEA):MeOH=80:20, 10 min; 1 mL/min). LCMS (ESI) [M+H] ⁺ = 487.2, Rt = 1.375 min, Method = J; ¹ H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.16 (s, 1H), 8.51 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.53 (s, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 5.72 (d, J = 3.0 Hz, 1H), 4.30-4.25 (m, 2H), 3.80 (s, 3H), 3.40-3.30 (m, 2H), 2.40-2.35 (m, 1H), 2.19-2.15 (m, 1H), 1.92 (s, 3H), 1.59-1.46 (m, 1H), 1.32-1.15 (m, 2H), 0.89-0.80 (m, J=7.3 Hz, 3H).
Example 108
3-(3-((1S,2S,3S)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-7-fluoroisoquinolin-6-yl)-4-methylpyridine 1-oxide and 3-(3-((1S,2R,3S)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-7-fluoroisoquinolin-6-yl)-4-methylpyridine 1-oxide (Compound 302a and Compound 302b)

Step 1: 3-Bromo-4-methyl-1-oxide-pyridin-1-ium

A solution of 3-bromo-4-methylpyridine (1 g, 5.8 mmol) and meta-chloroperbenzoic acid (1.5 g, 8.7 mmol) in dichloromethane (15 mL) was stirred at 20° C. for 2 hours. The reaction solution was quenched with a solution of sodium thiosulfate and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 3-bromo-4-methyl-1-oxide-pyridin-1-ium (1 g, crude) as a yellow solid. LCMS (ESI) [M+H] ⁺ =187.
Step 2: 7-Fluoro-6-(4-methyl-1-oxide-pyridin-1-ium-3-yl)isoquinolin-3-amine

A solution of 3-bromo-4-methyl-1-oxide-pyridin-1-ium (300 mg, 1.6 mmol), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-amine (456 mg, 1.6 mmol), Pd(dppf)Cl ₂ (119 mg, 0.2 mmol) and K ₂ CO ₃ (223 mg, 1.6 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred for 2 h at 90° C. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10/1) to give 7-fluoro-6-(4-methyl-1-oxide-pyridin-1-ium-3-yl)isoquinolin-3-amine (145 mg, 0.5 mmol, 33.7%) as a brown solid: LCMS (ESI) [M+H] ⁺ =270.1.
Step 3: 3-(3-((1S,2S,3S)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-7-fluoroisoquinolin-6-yl)-4-methylpyridine 1-oxide and 3-(3-((1S,2R,3S)-2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamido)-7-fluoroisoquinolin-6-yl)-4-methylpyridine 1-oxide

A solution of 7-fluoro-6-(4-methyl-1-oxide-pyridin-1-ium-3-yl)isoquinolin-3-amine (50 mg, 0.2 mmol), 2-ethyl-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxylic acid (38 mg, 0.20 mmol) and pyridine (29 mg, 0.4 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 30 minutes. Propylphosphonic anhydride (88 mg, 0.3 mmol) was added slowly at 0° C. The resulting solution was heated at 50° C. for 4 hours. The resulting solution was concentrated in vacuum. The residue was purified by reverse phase column (acetonitrile/1% NH ₄ HCO ₃ in water =2/1) to give a mixture of stereoisomers. The mixture was separated by chiral HPLC to give two stereoisomers. The pyrazole is trans to the amide; ethyl relative stereochemistry was arbitrarily assigned; all absolute stereochemistry was arbitrarily assigned.

Isomer 1 (compound 302a) (43 mg, 52% yield): Retention time: 2.628 min (Repaired Chiral-IA, 0.46*5 cm; 3 μm; (Hex:DCM=1:1) (0.1% DEA):IPA=50:50, 6 min; 1.0 ml/min). LCMS (ESI) [M+H] ⁺ =446.2, Rt=1.453 min, Method=J; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 9.21 (s, 1H), 8.55 (s, 1H), 8.31-8.20 (m, 2H), 8.03 (d, J=8.8 Hz, 2H), 7.54 (s, 1H), 7.44 (d, J=6.6 Hz, 1H), 7.30 (s, 1H), 3.80 (s, 3H), 2.36 (dd, J=8.9, 4.6 Hz, 1H), 2.20 (t, J=4.8 Hz, 1H), 2.13 (s, 3H), 1.61-1.46 (m, 1H), 1.30-1.16 (m, 2H), 0.90 (t, J=7.3 Hz, 3H).

Isomer 2 (compound 302b) (2 mg, 2.4% yield): Retention time: 4.063 min (Repaired Chiral-IA, 0.46*5 cm; 3 μm; (Hex:DCM=1:1) (0.1% DEA):IPA=50:50, 6 min; 1.0 ml/min). LCMS (ESI) [M+H] ⁺ =446.2, Rt=1.453 min, Method=J; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 9.21 (s, 1H), 8.55 (s, 1H), 8.31-8.20 (m, 2H), 8.03 (d, J=8.8 Hz, 2H), 7.54 (s, 1H), 7.44 (d, J=6.6 Hz, 1H), 7.30 (s, 1H), 3.80 (s, 3H), 2.36 (dd, J=8.9, 4.6 Hz, 1H), 2.20 (t, J=4.8 Hz, 1H), 2.13 (s, 3H), 1.61-1.46 (m, 1H), 1.30-1.16 (m, 2H), 0.90 (t, J=7.3 Hz, 3H).
Example 109
Tetrahydro-2H-pyran-4-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 103)

Synthesized following a procedure similar to that described above according to general synthesis method. LCMS (ESI) [M+H] ⁺ = 439.2, Rt = 3.937 min, method = N; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.11 (s, 1H), 8.21 (s, 1H), 7.92 (d, J = 10.0 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.37 (s, 1H), 5.72 (t, J = 2.7 Hz, 1H), 4.91 (dq, J = 8.9, 4.4 Hz, 1H), 4.30 (t, J = 4.4 Hz, 2H), 3.89-3.84 (m, 2H), 3.51-3.46 (m, 2H), 3.38-3.35 (m, 3H), 1.95 (dd, J=12.9, 4.0 Hz, 2H), 1.91 (d, J=1.9 Hz, 3H), 1.66-1.58 (m, 2H).
Example 110
1-Cyclopropyl-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea (Compound 207)

Synthesized following a procedure similar to that described above according to general synthetic method: LCMS (ESI) [M+H] ⁺ = 394.2, Rt = 2.006 min, Method = J; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.90 (s, 1H), 8.11 (s, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 7.35 (s, 1H), 7.09 (s, 1H), 5.71 (s, 1H), 4.28 (s, 2H), 1.89 (s, 3H), 0.65 (d, 4H).
Example 111

生物学的実施例 Additional compounds were synthesized following the general synthetic methods described herein and following procedures similar to those described above. LC/MS analytical data is provided in Table A1.

Biological Examples

Representative compounds of formula (I) were tested to assess compound inhibition of HPK-1.
Example B1: HPK1-FL HTRF Enzyme Assay ("HTRF")

Assay principle:
HPK-FL enzyme phosphorylated biotin-SLP-76 in the presence of ATP at 1 mM and various concentrations of test compound. Product was detected by FRET using Eu-anti-pSLP76 Ab and SA-XL665. See also www.cisbio.com/HTRF for further HTRF technical information.

Instrumentation: Echo 555 compound dispenser; Agilent Bravo; Perkin Elmer Envision.

Final assay conditions:
HPK full length, T165E S171E: 0.125 nM
Biotin-SLP76: 100 nM
ATP: 1 mM (ATP Km = 20 μM)
Eu-anti-pSLP76: 2 nM
SA-XL665: 8.3 nM
Preincubation time: 30 min. Kinase reaction time: 60 min. Temperature: ambient. Total volume: 12 μl.
ATP ^app Km: 17.7 μM

material:
Assay plate: White ProxiPlate 384 F (PerkinElmer Catalog No. 6008289)
Kinase: HPK full-length double mutant Substrate: Biotin-SLP76
ATP: 100 mM ATP
BSG: 2% BSG
DMSO: DMSO (Sigma Cat. No. 34869-100ML)
Reaction buffer: _H2O /50 mM HEPES, pH 7.5/10 mM MgCl2/ ₂ mM TCEP/0.01% Brij-35/0.01% BSG
Detection mix: Eu-anti-pSLP76/SA-XL665 (Cisbio, #610SAXAC)
Assay procedure for Ki measurement:

To a 384-well Proxiplate spotted with 80 nL of compound or DMSO, 4 μL/well of Kinase Mix was added. The mixture was pre-incubated for 30 minutes before mixing with 4 μL/well of Substrate Mix. The solution was incubated for 60 minutes before adding 4 μL/well of Detection Mix. The solution was incubated for an additional 60 minutes. The plate was then loaded onto a Perkin Elmer Envision and the TR-FRET signal was measured at 615 and 665 nm. The 665/620 ratio was used to calculate the percent activity at each concentration of compound.
Example B2: HPK1 Lantha Binding Assay ("Lanth")

手順：
Ｉ．化合物の希釈：

procedure:
I. Compound Dilution:

Test compounds were diluted using a Bravo liquid handling platform by preparing 12.5 μL/well of 5 mM compound (100X) in columns 2 and 13, 10 μL/well of DMSO in columns 3-12, 14-23, and wells A1-H1 and I24-P24 of the compound plate. For reference compounds, the top concentration was 1 mM. 10 μL 2 mM staurosporine was added to the plate in wells J1-P1 and A24-H24. An eleven point 5-fold compound serial dilution was performed using the Bravo liquid handling platform. 2.5 μL of solution in columns 2 and 13 was transferred from the plate to 10 μL of DMSO in columns 3 and 14, etc. The compound plate was centrifuged at 2500 rpm for 1 minute. 80 nl of compound was transferred from the compound plate to the assay plate using an Echo liquid handler system. One compound plate produces two assay plates. Each assay plate was sealed and stored in a _N2 cabinet.
II. Assay Conditions:

The following assay concentrations and times were used: 2 nM HPK1, 2 nM Eu-anti-GST Ab, and 15 nM Tracer222 (60 min incubation time).
III. HPK Lantha Binding Assay:

For the binding assay, 4 μL of 2× HPK1 and Eu-anti-GST antibodies were added to each well of the assay using the Multidrop reagent dispenser. The solutions were incubated for 1 hour in a 23° C. incubator. To each well of the assay plate, 4 μL of 2× Tracer-222 was added using the Multidrop reagent dispenser. The solutions were again incubated for 1 hour in a 23° C. incubator. Assay results were read using an Envision plate reader with the following parameters: TR_FRET, 340ex/615 and 665em; delay of 100 μsec; and integration of 200 μsec.
IV. analysis:

The Ki of the compounds was analyzed using the XL-fit Morrison ki fitting model.
a. Fit = (1 - ((((E+x)+(Ki*(1+(S/Kd)))) - (((((E+x)+(Ki*(1+(S/Kd))))^2) - ((4*E)*x))^0.5))/(2*E)))
res = (y-fit)
b. Parameters:
E = enzyme concentration, S = Tracer222 concentration, Kd = Tracer222 Kd
All measurements are reported using the same units (nM).

実施例Ｂ３：ヒトＴ細胞 ＩＬ２誘導アッセイ Exemplary compounds were tested in the HTRF binding assay and the measured K _i values are listed in Table B1.

Example B3: Human T cell IL2 induction assay

Assay principle: Anti-CD3 and anti-CD28 activate TCR signaling in primary human pan-T cells leading to IL-2 promoter induction. Secreted IL-2 in cell culture supernatants is detected by electrochemiluminescence using a capture antibody against IL-2 and a SULFO-tagged anti-IL-2 antibody. For further information on electrochemiluminescence technology, see also www.mesoscale.com.

Assay procedure: Incubate primary human pan T cells with various concentrations of test compound for 30 minutes in a humidified incubator at 37°C and 5% _CO2 . Transfer cells to plates pre-coated with a fixed concentration of anti-human CD3 (individual determination for each donor lot) and add soluble anti-human CD28 (final concentration = 1 μg/mL). Stimulate cells for 4 hours in a humidified incubator at 37°C and 5% _CO2 . Transfer 25 μL of supernatant to MSD single slot plate pre-coated with anti-human IL-2 antibody. Incubate MSD plate overnight at 4°C with gentle shaking. Wash MSD plate 4 times with wash buffer. Add sulfo-tagged detection antibody diluted 1:50 and incubate for 2 hours at room temperature with shaking. Wash MSD plate 4 times with wash buffer and add 150 μL 2X MSD read buffer. Read on MSD instrument. Data are normalized to stimulated/untreated controls and percent activity at each compound concentration is calculated.

material:
Frozen primary human pan T cells (StemCell Technologies #70024)
Anti-human CD3 (OKT3 clone) (eBioscience #16-0037-81)
Anti-human CD28 (CD28.2 clone) (BD #555725)
96-well Human IL-2 Tissue Culture Kit (MSD #K151AHB-4)

instrumentation:
Biomek FX (Beckman Coulter) for liquid handling
MSD SECTOR S 600 (Meso Scale Discovery)

実施例Ｂ４：ｐＳＬＰ７６アッセイ Representative compounds of formula (I) were tested in the human T cell IL-2 induction assay, and the percent increase measured in IL-2 in cells treated with the test compound compared to untreated cells is shown for the particular compound in Table B2.

Example B4: pSLP76 Assay

Assay principle: Anti-CD3 activates TCR signaling in human Jurkat cells, leading to phosphorylation of SLP-76 at S376 by HPK-1. Phospho-SLP76 (S376) is detected by sandwich ELISA using an anti-pSLP76 (S376) capture antibody and a biotinylated anti-SLP76 detection antibody.

material:
Jurkat, clone E6-1 (ATCC Cat# TIB-152)
Anti-CD3 DynaBeads (Invitrogen, Cat# 111.51D)
Anti-pSLP76 (S376) rabbit monoclonal (Genentech)
Biotinylated anti-SLP76 rabbit polyclonal (Thermo, biotin conjugation was performed in-house)
Streptavidin-Horseradish Peroxidase (GE, Cat# RPN4401V)
TMB Substrate (Cell Signaling, Cat# 7004)
STOP solution (Cell Signaling, Cat# 7002)
Assay procedure:

Incubate Jurkat cells with various concentrations of test compounds for 30 minutes in a humidified incubator at 37°C and 5% _CO2 . Add anti-CD3 DynaBeads at a 4:1 bead:cell ratio. Stimulate cells for 10 minutes in a humidified incubator at 37°C and 5% _CO2 . Add cold lysis buffer and incubate for 30 minutes at 4°C on a shaker. Transfer cell lysates to pre-blocked ELISA plates coated with capture antibodies. Incubate for 2 hours at room temperature with shaking. Wash ELISA plates 5 times with wash buffer and add 25 μl of biotinylated detection antibody at a final concentration of 0.5 μg/ml. Incubate for 1 hour at room temperature with shaking. Wash ELISA plates 5 times with wash buffer and add 25 μl of streptavidin enzyme conjugate at a final dilution of 1:8000. Incubate for 20 minutes at room temperature with shaking. Wash ELISA plate 5 times with wash buffer and add 25 μl of TMB substrate solution. Incubate for 20 minutes at room temperature in the dark with shaking. Add 25 μl of STOP solution and read absorbance at 450 nm in SoftMax Pro.
Example B5: Permeability assay

The cell permeability of compounds of interest was evaluated in the gMDCKI cell line, a modified MDCKI (Madin-Darby canine kidney) originally obtained from the American Type Culture Collection (Manassa, VA) and produced at Genentech. Cells were seeded in 24-well Millicell plates (Millipore, Billerca, MA) (polyethylene terephthalate membrane, 1 mm pore size) at a seeding density of ^2.5x105 cells/mL at 37°C with 5% _CO2 and 95% humidity 4 days prior to use. Test articles were tested at 10 μM in the apical to basal (A-B) and basolateral to apical (B-A) directions. Test compounds were dissolved in transport buffer consisting of Hank's balanced salt solution and 10 mM HEPES (Invitrogen Corporation, Grand Island, NY). Transepithelial electrical resistance (TEER) and Lucifer Yellow (LY) permeability were used to monitor monolayer integrity at the beginning and end of the experiment, respectively. Test articles were analyzed by LC-MS/MS.

The apparent permeability (P _app ) in the AB and BA directions at the tip was calculated as follows after 2 hours of incubation: P _app =(dQ/dt)·(1/AC ₀ )
where dQ/dt = rate of compound appearance in the receiver compartment; A = surface area of the insert; C ₀ = initial substrate concentration at T ₀ . The efflux ratio (ER) is calculated as:
(P _app , B-A/P _app , A-B)
It is calculated as:
Example B6: Hepatocyte stability assay

The metabolic stability of compounds is evaluated using a hepatocyte stability assay. Cryopreserved human hepatocytes from 10 donor pools are rapidly thawed at 37° C. and suspended in pre-warmed In VitroGRO™ HT medium, then centrifuged at 100×g for 10 min at room temperature. The supernatant is discarded and the cells are resuspended in 5 mL of Dulbecco's Modified Eagle Medium (DMEM) medium. Cell viability in suspension is counted with a Hepatometer® Vision (Lonza, NC) and viable cells are then adjusted to 1.0×10 ⁶ cells/mL in DMEM. Compounds are first diluted to 2 μM in DMEM medium, then aliquots of 125 μL of drug-containing medium are transferred to 96-well non-coated plates. Incubation is initiated by the addition of 125 μL of hepatocyte suspension to obtain a total incubation volume of 250 μL. The final concentration of each compound is 1 μM and the final cell density is 0.5×10 ⁶ cells/mL. Incubations are carried out at 37° C. in a humidified incubator. Aliquots of 50 μL of incubation medium are taken at different time intervals (0, 60, 120 and 180 min) and immediately mixed with 100 μL of ice-cold acetonitrile containing 50 nM propranolol (internal standard). Samples are then centrifuged at 10,000×g for 10 min and 80 μL of supernatant is taken and diluted with 160 μL of water before LC/MS-MS analysis. In vitro intrinsic clearance and scaled hepatic clearance were determined as described in Obach et al. J. Pharmacol. Exp. Ther. 283:46-58 (1997).
Example B7: Pharmacokinetic (PK) studies

Pharmacokinetic studies in rats: Male Sprague Dawley rats obtained from Lingchang/Vital River Laboratory Animal Technology Co., Ltd. (Shanghai/Beijing, P.R. China) with body weights ranging from 200 g to 300 g were used in the PK study. A group of three rats received an intravenous bolus (IV) dose of 1 mg/kg of the test article in a solution formulation, and another group of three rats received oral (PO) doses of 2 or 5 mg/kg of the test article as a suspension or solution in 0.5% methylcellulose with 0.2% Tween 80 (MCT). Blood samples (250 μL/time point) were collected stepwise from each rat via a catheter in the femoral artery at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 6, and 8 hours after IV or PO dosing. Blood samples were collected into pre-chilled tubes containing potassium (K2) EDTA and centrifuged at 3,200 g for 10 minutes at 2-8°C to collect plasma within 1 hour of collection. Plasma samples were stored at -70°C until LC/MS/MS analysis. Concentrations in each plasma sample were determined by non-validated LC/MS/MS. Data were acquired using multiple reaction monitoring (MRM) with unique transitions monitored for each compound.

Pharmacokinetic Analysis: Pharmacokinetic parameters were calculated by noncompartmental methods as described by Gibaldi and Perrier (Gibaldi and Perrier, 1982) using Phoenix® WinNonlin® version 6.4 (Certara L.P.). After PO administration, percent bioavailability (% F) was determined for each animal by dividing the dose-normalized area under the plasma concentration-time curve extrapolated to infinity (AUC _inf ) obtained after each PO dose by the mean dose-normalized AUC _inf of animals dosed by IV injection. All PK parameters are presented as mean ± standard deviation (SD).

It should be noted that the term "a" or "an" refers to one or more of that component. For example, "a polypeptide" is understood to refer to one or more polypeptides. To that end, the terms "a" (or "an"), "one or more," or "at least one" can be used interchangeably herein.

All technical and scientific terms used herein have the same meaning. Efforts have been made to ensure accuracy in numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations exist.

Throughout this specification and the claims, the words "comprise/comprises/comprising" are used in a non-exclusive sense unless the context requires otherwise. The embodiments described herein are understood to include "consisting of" and/or "consisting essentially of" embodiments.

As used herein, the term "about," when referring to a value, is meant to encompass variations from the stated amount, in some embodiments, ±50%, in some embodiments, ±20%, in some embodiments, ±10%, in some embodiments, ±5%, in some embodiments, ±1%, in some embodiments, ±0.5%, and in some embodiments, ±0.1%, such variations being appropriate for practicing the disclosed methods or using the disclosed compositions.

When a range of values is provided, unless the context clearly indicates otherwise, it is understood that each intervening value between the upper and lower limits, to one-tenth of the unit of the lower limit, and each intervening value within the stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges that may be independently included in smaller ranges are also encompassed within the invention, subject to any specifically excluded limit in the stated range. When the stated range includes one or both of the limits, ranges excluding one or both of the included limits are also encompassed within the invention.

Many modifications of the inventions described herein, as well as other embodiments of the inventions, will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the accompanying drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims (21)

Formula (I)

(Wherein,
R ¹ is hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _1-6 haloalkyl, C _3-4 cycloalkyl, -O(C _1-6 alkyl), or -O(C _1-6 haloalkyl);
R ¹⁵ is —OR ¹⁶ , —SR ¹⁶ , —NR ¹⁷ R ¹⁸ , or D;
each R ¹⁶ is independently a C _1-6 alkyl, a C _3-10 cycloalkyl, or a 3- to 14-membered heterocyclyl, and said C _1-6 alkyl, C _3-10 cycloalkyl, and 3- to 14-membered heterocyclyl of R ¹⁶ are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
R ¹⁷ is hydrogen or C _1-6 alkyl;
R ¹⁸ is a 3-14 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; a C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ; or a C _1-6 alkyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
or R ¹⁷ and R ¹⁸ together with the nitrogen atom to which they are attached form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ ;
D is

where the wavy line represents the point of attachment to the parent structure;
R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ are independently hydrogen or R ¹⁰ , and optionally two of R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ together with the carbon atom to which they are attached form a C _3-8 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ or a 3-10 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R ¹⁰ , with the proviso that at least one of R ³⁰ , R ³¹ , R ³² , R ³³ and R ³⁴ is other than hydrogen;
R ³ is hydrogen, halogen, cyano, C _1-6 alkyl, C _3-8 cycloalkyl, 3- to 14-membered heterocyclyl, or -OR ⁷ , wherein said C _1-6 alkyl, C _3-8 cycloalkyl, and 3- to 14-membered heterocyclyl of R ³ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
^R4 is

is selected from the group consisting of
R ⁵ is hydrogen, halogen, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-14 aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, -C(O)R ⁶ , -C(O)OR ⁷ , -C(O)NR ^8a R ^8b , -OR ⁷ , -OC(O)R ⁶ , -OC(O)NR ^8a R ^8b , -SR ⁷ , -S(O)R ⁹ , -S(O) ₂ R ⁹ , -S(O) ₂ NR ^8a R ^8b , -P(O)R ^9a R ^9b , -NR ^8a R ^8b , -N(R ⁸ )C(O)R ⁶ , -N(R ⁸ )C(O)OR ⁷ , —N(R ⁸ )C(O)NR ^8a R ^8b , —N(R ⁸ )S(O) ₂ R ⁹ , or —N(R ⁸ )S(O) ₂ NR ^8a R ^8b , wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-14 aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl of R ⁵ are each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
each R ⁶ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, or 3-12 membered heterocyclyl, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-14 membered heteroaryl, and 3-12 membered heterocyclyl of R ⁶ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
each R ⁷ is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl of R ⁷ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
Each R ⁸ is independently hydrogen or C _1-6 alkyl;
each R ^8a and R ^8b is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl of R ^8a and R ^8b are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
or R ^8a and R ^8b together with the nitrogen atom to which they are attached form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
each R ⁹ is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl of R ⁹ are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
each R ^9a and R ^9b is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclyl, or -O-C _1-6 alkyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl ^of R 9a and R ^9b are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
or R ^9a and R ^9b together with the phosphorus atom to which they are attached form a 4-12 membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ¹⁰ ;
Each R ¹⁰ is independently selected from oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, halogen, cyano, -C(O)R ^a , -C(O)OR ^b , -C(O)NR ^c R ^d , -OR ^b , -OC(O)R ^a , -OC(O)NR ^c R ^d , -SR ^b , -S(O)R ^e , -S(O) ₂ R ^e , -S(O)(═NH)R ^e , -S(O) ₂ NR ^c R ^d , -NR ^c R ^d , -N(R ^f )C(O)R ^a , -N(R ^f )C(O)OR ^b , —N(R ^f )C(O)NR ^c R ^d , —N(R ^f )S(O) ₂ R ^e , —N(R ^f )S(O) ₂ NR ^c R ^d , or —P(O)R ^g R ^h , wherein ^the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl of R 10 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
Each R ^a is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^a are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
each R ^b is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R ^b are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
Each R ^c and R ^d is independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, and said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl of R ^c and R ^d are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
or R ^c and R ^d together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
Each R ^e is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, and said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R ^e are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
Each R ^f is independently hydrogen or C _1-6 alkyl;
each R ^g and R ^h is independently C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or -O-C _1-6 alkyl, wherein said C _1-6 alkyl, C _3-8 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of ^R g and R ^h are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
or R ^g and R ^h together with the phosphorus atom to which they are attached form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹¹ ;
Each R ¹¹ is independently selected from oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, halogen, cyano, -C(O)R ^a1 , -C(O)OR ^b1 , -C(O)NR ^c1 R ^d1 , -OR ^b1 , -OC(O)R ^a1 , -OC(O)NR ^c1 R ^d1 , -SR ^b1 , -S(O)R ^e1 , -S(O) ₂ R ^e1 , -S(O) ₂ NR ^c1 R ^d1 , -NR ^c1 R ^d1 , -N(R ^f1 )C(O)R ^a1 , -N(R ^f1 )C(O)OR ^b1 , -N(R ^f1 )C(O)NR ^c1 R ^d1 , -N(R ^f1 )S(O) ₂ R ^e1 , -N(R ^f1 )S(O) ₂ NR ^c1 R ^d1 , or -P(O)R ^g1 R ^h1 , wherein the C _1-6 alkyl, C _2-6 alkenyl, C ^2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 14 _- membered heteroaryl, and 3- to 14-membered heterocyclyl of R 11 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
Each R ^a1 is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6} alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _6-10 aryl, _5-10 membered heteroaryl, and 3-8 membered heterocyclyl of R ^a1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
Each R ^b1 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R ^b1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
Each R ^c1 and R ^d1 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R ^c1 and R ^d1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
or R ^c1 and R ^d1 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
Each R ^e1 is independently C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, and said C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R ^e1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
Each R ^f1 is independently hydrogen or C _1-6 alkyl;
Each R ^g1 and R ^h1 is independently C _1-6 ^alkyl , C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or -O-C _1-6 alkyl, wherein said C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R g1 and R ^h1 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
or R ^g1 and R ^h1 together with the phosphorus atom to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹² ;
Each R ¹² is independently selected from oxo, C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, halogen, cyano, -C(O)R ^a2 , -C(O)OR ^b2 , -C(O)NR ^c2 R ^d2 , -OR ^b2 , -OC(O)R ^a2 , -OC(O)NR ^c2 R ^d2 , -S(O) ₂ R ^e2 , -S(O) ₂ NR ^c2 R ^d2 , -NR ^c2 R ^d2 , -N(R ^f2 )C(O)R ^a2 , -N(R ^f2 )C(O)OR ^b2 , -N(R ^f2 )C(O)NR ^c2 R ^d2 , -N(R ^f2 )S(O) ₂ R ^e2 , -N(R ^f2 )S(O) ₂ NR ^c2 R ^d2 , or -P(O)R ^g2 R ^h2 , wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of R ¹² are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
Each R ^a2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of R ^a2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
each R ^b2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3- to 6-membered heterocyclyl, and said C _1-6 alkyl, C _3-6 cycloalkyl, and 3- to 6-membered heterocyclyl of R ^b2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
Each R ^c2 and R ^d2 is independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl, or 3- to 8-membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, and 3- to 8-membered heterocyclyl of R ^c2 and R ^d2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
or R ^c2 and R ^d2 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
Each R ^e2 is independently C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, and the C _1-6 alkyl, C _3-6 cycloalkyl, C ₆ aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl of R ^e2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
Each R ^f2 is independently hydrogen or C _1-6 alkyl;
each R ^g2 and R ^h2 is independently C _1-6 alkyl, C _3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or -O-C _1-6 alkyl, wherein said C _1-6 alkyl, C _3-6 cycloalkyl, and 3- to 8-membered heterocyclyl of R ^g2 and R ^h2 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ ;
or R ^g2 and R ^h2 , together with the phosphorus atom to which they are attached, form a 4-6 membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ¹³ , and each R ¹³ is independently oxo, halogen, hydroxyl, —O(C _1-6 alkyl), cyano, C _1-6 alkyl, or C _1-6 haloalkyl.
or a pharma- ceutically acceptable salt thereof. 2. The compound of claim 1 , or a pharma- ceutically acceptable salt thereof, wherein ^R3 is hydrogen. 3. The compound according to claim 1 or 2 , wherein R ¹⁵ is --OR ¹⁶ , or a pharma- ceutically acceptable salt thereof . ^R16 is

where the wavy line represents the point of attachment to the parent structure.
The compound according to any one of claims 1 to 3 , or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: R ¹⁵ is -NR ¹⁷ R ¹⁸ , where R ¹⁷ is hydrogen and R ¹⁸ is

where the wavy line represents the point of attachment to the parent structure.
3. The compound of claim 1 or 2 , selected from the group consisting of: ^R18 is,

where the wavy line represents the point of attachment to the parent structure.
3. The compound of claim 1 or 2 , selected from the group consisting of: ^R18 is,

where the wavy line represents the point of attachment to the parent structure.
3. The compound of claim 1 or 2 , selected from the group consisting of: D.

3. The compound of claim 1 or 2 , wherein: The compound has formula (IA):

(wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ¹⁶ are as defined in claim 1 ).
2. The compound of claim 1 , which is a compound of the formula : The compound has formula (IB):

(wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ¹⁷ and R ¹⁸ are as defined in claim 1 ).
2. The compound of claim 1 , which is a compound of the formula : The compound has the formula (IC):

(wherein R ¹ , R ³ , R ⁴ , R ⁵ and D are as defined in claim 1 ).
2. The compound of claim 1 , which is a compound of the formula : The compound is
Cyclopropylmethyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
Tetrahydro-2H-pyran-4-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
1-acetylazetidin-3-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
1-(methylcarbamoyl)azetidin-3-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(3-fluoropyrrolidin-3-yl)methyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-(3-fluoropyrrolidin-3-yl)methyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-(3-fluoropyrrolidin-3-yl)methyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
Pyrrolidin-3-ylmethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-Pyrrolidin-3-ylmethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-Pyrrolidin-3-ylmethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
1-Oxa-7-azaspiro[4.4]nonan-3-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-1-Oxa-7-azaspiro[4.4]nonan-3-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-1-Oxa-7-azaspiro[4.4]nonan-3-yl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
Pyrrolidin-2-ylmethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-Pyrrolidin-2-ylmethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-Pyrrolidin-2-ylmethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-aminopropyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-2-aminopropyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-2-aminopropyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(4-fluoropiperidin-4-yl)methyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-aminoethyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
7-Azaspiro[3.5]nonan-2-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
3-Methoxybutyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-3-Methoxybutyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-3-Methoxybutyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
Adamantan-2-yl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(Tetrahydro-2H-pyran-2-yl)methyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-(tetrahydro-2H-pyran-2-yl)methyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-(Tetrahydro-2H-pyran-2-yl)methyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-(methylsulfonyl)ethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2,2,2-trifluoroethyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-(pyridin-2-yl)ethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
Neopentyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-Azabicyclo[2.2.1]heptan-5-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(2-Azabicyclo[3.1.0]hexan-1-yl)methyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-(2A azabicyclo[3.1.0]hexan-1-yl)methyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-(2-Azabicyclo[3.1.0]hexan-1-yl)methyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
6-Azaspiro[3.4]octan-1-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-6-Azaspiro[3.4]octan-1-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-6-Azaspiro[3.4]octan-1-yl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-(3-Azabicyclo[3.1.0]hexan-6-yl)ethyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-Azaspiro[3.3]heptan-6-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
trans-2-cyanocyclohexyl(8-chloro-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1S,2R)-2-cyanocyclohexyl(8-chloro-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1R,2S)-2-cyanocyclohexyl(8-chloro-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
trans-2-cyanocyclopentyl(8-chloro-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1R,2S)-2-cyanocyclopentyl(8-chloro-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1S,2R)-2-cyanocyclopentyl(8-chloro-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
trans-2-cyanocyclopentyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1R,2S)-2-cyanocyclopentyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1S,2R)-2-cyanocyclopentyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
3-Azabicyclo[3.1.0]hexan-6-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
1,1-dioxidothietan-3-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
1-(N-methylsulfamoyl)azetidin-3-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-Methyl-2-azaspiro[3.3]heptan-6-yl (7-fluoro-6-(4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)carbamate;
7-methyl-7-azaspiro[3.5]nonan-2-yl (7-fluoro-6-(4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)carbamate;
6-Azaspiro[3.4]octan-2-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(2r,4s)-6-Azaspiro[3.4]octan-2-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(2s,4r)-6-Azaspiro[3.4]octan-2-yl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
Piperidin-2-ylmethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-Piperidin-2-ylmethyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-Piperidin-2-ylmethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
3-Azabicyclo[3.1.0]hexan-1-yl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(R)-3-Azabicyclo[3.1.0]hexan-1-yl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(S)-3-Azabicyclo[3.1.0]hexan-1-yl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-(2-oxopyrrolidin-1-yl)ethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2,6-dimethylcyclohexyl(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-Methoxybenzyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
2-(trifluoromethyl)benzyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
(1-methyl-1H-imidazol-5-yl)methyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
1-(pyrimidin-2-yl)ethyl (7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate;
1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea;
(R)-1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea;
(S)-1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-(1-methyl-1H-pyrazol-4-yl)ethyl)urea;
1-(cyclopropylmethyl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea;
1-(1-cyanopropan-2-yl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea;
(R)-1-(1-cyanopropan-2-yl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea;
(S)-1-(1-cyanopropan-2-yl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea;
1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)urea;
1-(azetidin-3-yl)-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea;
1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(tetrahydrofuran-3-yl)urea;
(R)-1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(tetrahydrofuran-3-yl)urea;
(S)-1-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(tetrahydrofuran-3-yl)urea;
1-cyclopropyl-3-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)urea;
(1,3-trans)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide;
(1R,2S,3R)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide;
(1R,2R,3R)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide;
(1S,2S,3S)-2-ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide;
(1S,2R,3S)-2-Ethyl-N-(7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carboxamide
2. The compound of claim 1, selected from the group consisting of: A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient . 14. The pharmaceutical composition of claim 13 , further comprising a chemotherapeutic agent. A medicament for inhibiting HPK1 in a subject , comprising a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof , or a pharmaceutical composition according to claim 13 or 14 . A pharmaceutical for enhancing an immune response in a subject in need thereof , comprising a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof , or a pharmaceutical composition according to claim 13 or 14 . The pharmaceutical composition of claim 15 or 16 , wherein the subject has cancer. A pharmaceutical for treating an HPK1-dependent disorder , comprising the compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof , or the pharmaceutical composition according to claim 13 or 14 . The pharmaceutical composition of claim 18 , wherein the HPK1-dependent disorder is cancer. 20. The pharmaceutical of claim 17 or 19, wherein the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma . Use of a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 or 14 , in the manufacture of a medicament according to any one of claims 15 to 20 .